1
|
Li J, Ju M, Zheng D, Wan H, Sun Y, Zhao J, Zhou L, Yin Q, Kang W, Song Y, Xue S. Simultaneous analysis of 7 key mevalonate pathway intermediates using liquid chromatography-orbitrap mass spectrometry. Anal Biochem 2025; 701:115816. [PMID: 39956445 DOI: 10.1016/j.ab.2025.115816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
The mevalonate (MVA) pathway is a central metabolic route that converts mevalonate into isoprenoids, which are of crucial significance in various cellular processes. As no systematic approach had been developed and validated for the simultaneous estimation of these intermediate metabolites within the MVA pathway. In this research, a method was developed for the concurrent determination of 7 key intermediate metabolites in the MVA pathway based on ultra-high performance liquid chromatography (UPLC) coupled with a quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (HRMS). The developed UPLC-HRMS method based on the hydrophilic interaction liquid chromatography (HILIC) separation mode was successfully applied to the quantitative analysis of relevant key intermediate metabolites in wild type Escherichia coli (E. coli) BL21 (DE3) and the recombinant E. coli BL21 (DE3) system constructed by introducing all the genes of the MVA pathway into the strain. The above results can offer a reference for further studies on the MVA pathway.
Collapse
Affiliation(s)
- Jiani Li
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China; School of Bioengineering, Dalian University of Technology, Dalian, 116024, China
| | - Min Ju
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China; School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China
| | - Danni Zheng
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China; School of Bioengineering, Dalian University of Technology, Dalian, 116024, China
| | - Huihui Wan
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China.
| | - Yuming Sun
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China
| | - Jinfeng Zhao
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China
| | - Lina Zhou
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China
| | - Qingxin Yin
- Instrumental Analysis Center, Dalian University of Technology, Dalian, 116024, China
| | - Wei Kang
- School of Bioengineering, Dalian University of Technology, Dalian, 116024, China
| | - Yuming Song
- School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, China
| | - Song Xue
- School of Bioengineering, Dalian University of Technology, Dalian, 116024, China
| |
Collapse
|
2
|
Farías MA, Cancino FA, Navarro AJ, Duarte LF, Soto AA, Tognarelli EI, Ramm MJ, Alarcón-Zapata BN, Cordero J, San Martín S, Agurto-Muñoz C, Retamal-Díaz A, Riedel CA, Barrera NP, Bustamante L, Bueno SM, Kalergis AM, González PA. HSV-1 alters lipid metabolism and induces lipid droplet accumulation in functionally impaired mouse dendritic cells. iScience 2025; 28:112441. [PMID: 40343272 PMCID: PMC12059724 DOI: 10.1016/j.isci.2025.112441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 02/04/2025] [Accepted: 04/10/2025] [Indexed: 05/11/2025] Open
Abstract
Herpes simplex virus type 1 (HSV-1) significantly impairs dendritic cell (DC) function, ultimately eliciting the death of these cells. Here, we sought to assess whether HSV-1 modulates lipid metabolism in mouse DCs as a mechanism of immune evasion. For this, we performed RT-qPCR gene arrays with ingenuity pathway analysis (IPA), RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA), confocal microscopy, transmission electron microscopy, ultra-high-performance liquid chromatography-quadrupole time-of-flight (UHPLC-QTOF) analysis, pharmacological inhibition of eight lipid-metabolism-related enzymes in HSV-1-infected DCs, co-cultures between virus-specific transgenic CD4+ and CD8+ T cells and HSV-1-infected DCs, and in vivo assays with mice. We found that HSV-1 significantly alters lipid metabolism in DCs and induces lipid droplet (LD) accumulation in these cells. Pharmacological inhibition of two particular lipid metabolism enzymes was found to partially restore DC function. Overall, these results suggest that lipid metabolism plays an important role in the impairment of DC function by HSV-1.
Collapse
Affiliation(s)
- Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Felipe A. Cancino
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Areli J. Navarro
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luisa F. Duarte
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Abel A. Soto
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Eduardo I. Tognarelli
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Maximiliano J. Ramm
- Departamento de Análisis Instrumental, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
| | - Bárbara N. Alarcón-Zapata
- Departamento de Análisis Instrumental, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
| | - José Cordero
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sergio San Martín
- Grupo Interdisciplinario de Biotecnología Marina (GIBMAR), Centro de Biotecnología, Universidad de Concepción, Concepción, Chile
| | - Cristian Agurto-Muñoz
- Grupo Interdisciplinario de Biotecnología Marina (GIBMAR), Centro de Biotecnología, Universidad de Concepción, Concepción, Chile
| | - Angello Retamal-Díaz
- Millennium Institute on Immunology and Immunotherapy, Chile
- Departamento de Biotecnología, Facultad de Ciencias del Mar y de Recursos Biológicos, Universidad de Antofagasta, Antofagasta, Chile
- Centro de Investigación en Inmunología y Biotecnología Biomédica de Antofagasta, Hospital Clínico Universidad de Antofagasta, Antofagasta, Chile
| | - Claudia A. Riedel
- Millennium Institute on Immunology and Immunotherapy, Chile
- Centro de Investigación para la Resiliencia a Pandemias, Facultad Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Nelson P. Barrera
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Bustamante
- Departamento de Análisis Instrumental, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
| | - Susan M. Bueno
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| |
Collapse
|
3
|
Pecci F, Cognigni V, Giudice GC, Paoloni F, Cantini L, Saini KS, Abushukair HM, Naqash AR, Cortellini A, Mazzaschi G, Alia S, Membrino V, Araldi E, Tiseo M, Buti S, Vignini A, Berardi R. Unraveling the link between cholesterol and immune system in cancer: From biological mechanistic insights to clinical evidence. A narrative review. Crit Rev Oncol Hematol 2025; 209:104654. [PMID: 39923921 DOI: 10.1016/j.critrevonc.2025.104654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/29/2025] [Accepted: 02/04/2025] [Indexed: 02/11/2025] Open
Abstract
Cholesterol and its metabolism seem to be involved not only in cancer progression but also in immune cells activity. In this comprehensive review, we summarize preclinical, translational, and clinical evidence regarding the crucial role of cholesterol and its metabolism in regulating the immune response against cancer cells, shedding light on the multifaceted mechanisms by which cholesterol influences immune cell function and anti-tumor immunity. By synthesizing findings from preclinical studies, we have elucidated the impact of cholesterol on immune cell activation, differentiation, and effector functions. These investigations have revealed that cholesterol metabolism plays a pivotal role in shaping the immune response, with alterations in cholesterol levels directly impacting immune cell behavior and anti-tumor activity. All the steps related to cholesterol metabolism, including its de-novo synthesis, its influx and efflux mechanisms, as well as its metabolites, have a distinct impact on immune cells function and activity, which, if altered, might influence tumor progression. In addition, we have reviewed clinical studies investigating the role of circulating cholesterol on outcomes of patients with advanced tumors treated with immune checkpoint inhibitors, highlighting again in a clinical scenario the correlation between cholesterol and the immune system. Overall, our review emphasizes the importance of cholesterol and its metabolism in orchestrating the immune response against cancer cells. Herein we have provided a comprehensive overview of this emerging field by illustrating the intricate interplay between cholesterol and immune system.
Collapse
Affiliation(s)
- Federica Pecci
- Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
| | - Valeria Cognigni
- Department of Medical Oncology, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy
| | - Giulia Claire Giudice
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Francesco Paoloni
- Department of Medical Oncology, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy
| | | | - Kamal S Saini
- Fortrea, Inc., Durham, NC, USA; Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Hassan Mohammed Abushukair
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, USA; Division of Oncology Sciences, University of Oklahoma Health Sciences Center, USA
| | - Abdul Rafeh Naqash
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, USA; Division of Oncology Sciences, University of Oklahoma Health Sciences Center, USA; Medical Oncology/TSET Phase 1 Program, Stephenson Cancer Center, The University of Oklahoma, Oklahoma City, OK, USA
| | - Alessio Cortellini
- Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy; Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK
| | - Giulia Mazzaschi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Sonila Alia
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
| | - Valentina Membrino
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy
| | - Elisa Araldi
- Systems Medicine Laboratory, Department of Medicine and Surgery (DiMeC), Università degli Studi di Parma, Parma, Italy; Preventive Cardiology and Preventive Medicine, University Medical Center Of The Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Germany
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Sebastiano Buti
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Arianna Vignini
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica delle Marche, Ancona, Italy; Research Center of Health Education and Health Promotion, Università Politecnica delle Marche, Ancona, Italy
| | - Rossana Berardi
- Department of Medical Oncology, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy
| |
Collapse
|
4
|
Zheng L, Nie W, Wang S, Yang L, Hu F, Ma M, Cheng L, Lu J, Zhang B, Xu J, Li Y, Shen Y, Zhang W, Zhong R, Chu T, Han B, Zheng X, Zhong H, Zhang X. Metabolomic machine learning-based model predicts efficacy of chemoimmunotherapy for advanced lung squamous cell carcinoma. Front Immunol 2025; 16:1545976. [PMID: 40242771 PMCID: PMC12000773 DOI: 10.3389/fimmu.2025.1545976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 03/13/2025] [Indexed: 04/18/2025] Open
Abstract
Background Unlike lung adenocarcinoma, patients with advanced squamous carcinoma exhibit a low proportion of driver gene positivity, with fewer effective treatment strategies available. Chemoimmunotherapy has now become the standard first-line treatment for individuals diagnosed with advanced lung squamous carcinoma. Serum metabolomics holds significant potential for application in predicting responses to chemoimmunotherapy and is capable of identifying and validating potential biomarkers. The aim of our study was to establish a model that can predict the prognosis of chemoimmunotherapy in patients with advanced lung squamous cell carcinoma, integrating metabolomics with machine learning techniques. Methods We collected 79 serum samples from patients with advanced lung squamous cell carcinoma before receiving combined immunotherapy and performed untargeted metabolomics analysis. Patients were divided into non-response (NR) and response (R) groups according to overall survival (OS), and prognostic models were constructed and validated using different machine learning methods. The patients were further categorized into high-risk and low-risk groups based on the median risk score, to assess the model's predictive performance. Results There were significant differences in metabolites and metabolic pathways between NR and R groups, and 117 differential metabolites were preliminarily screened (p < 0.05, VIP > 1). Further, least absolute shrinkage and selection operator (LASSO) and random forest (RF) were used to identify metabolites, and then their common metabolites were used as the best biomarkers to build a prediction model containing 8 differential metabolites. Based on these biomarkers, RF, support vector machine (SVM) and logistic regression were used to randomly divide patients into training and validation sets in a 7:3 ratio, respectively. We found that the RF method resulted in area under curves (AUCs) of 0.973 and 0.944 for the training and validation sets, respectively, with the best predictive performance. Subsequently, both OS and progression-free survival (PFS) were notably reduced in the high-risk group when contrasted with the low-risk group. Conclusions We developed a model containing 8 metabolites based on metabolomics and machine learning that may predict survival outcomes in patients with advanced lung squamous cell carcinoma undergoing chemoimmunotherapy, helping to more accurately assess efficacy and prognosis in clinical practice.
Collapse
Affiliation(s)
- Liang Zheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Nie
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuyuan Wang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Yang
- Department of Ultrasonography, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Hu
- Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, Hangzhou, China
- Hangzhou Institute of Medicine (HlM), Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Meili Ma
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Cheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianlin Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Li
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinchen Shen
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runbo Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianqing Chu
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baohui Han
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxuan Zheng
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Respiratory Endoscopy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Zhong
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueyan Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
5
|
Perdomo-Celis F, Passaes C, Monceaux V, Lambotte O, Costagliola D, Chevalier MF, Weiss L, Sáez-Cirión A. Impact of rosuvastatin on the memory potential and functionality of CD8 + T cells from people with HIV. EBioMedicine 2025; 114:105672. [PMID: 40158388 PMCID: PMC11995788 DOI: 10.1016/j.ebiom.2025.105672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Virus-specific CD8+ T cells play a major role in the natural control of HIV infection, linked to memory-like features such as high survival capacity and polyfunctionality. However, virus-specific CD8+ T cells from HIV non-controllers exhibit an effector-like and exhausted profile, with limited antiviral potential. Metabolic reprogramming of cells from non-controllers could reinvigorate their functional capacities. Considering the implication of the cholesterol pathway in the induction of T cell exhaustion, here we evaluated the impact of rosuvastatin, an inhibitor of cholesterol synthesis, on the functionality and memory profile of HIV-specific CD8+ T cells from people on antiretroviral treatment. METHODS We analysed samples from 10 individuals with HIV-1 on ART who participated in the IMEA 043-CESAR trial and received rosuvastatin for 12 weeks. We explored whether rosuvastatin treatment was accompanied by changes in the memory potential of CD8+ T cells. We evaluated the phenotype and functionality of total and HIV-specific CD8+ T cells before, during, and after treatment with rosuvastatin. A mixed effects model was used for repeated measures and corrected for multiple comparisons. FINDINGS Total and HIV-specific CD8+ T cell survival and functionality were enhanced in individuals who received a 12-week course of rosuvastatin, with a consistent increase in polyfunctional IFN-γ+ TNF-α+ cells. The superior CD8+ T cell functionality after rosuvastatin treatment was associated with intrinsic metabolic changes, including the decrease of fatty acid uptake, as well as a reduction in effector/exhaustion markers. Changes in the characteristics of CD8+ T cells coincided with the duration of rosuvastatin administration, and most effects waned after the cessation of the treatment. INTERPRETATION CD8+ T cell metabolic reprogramming by targeting the cholesterol pathway, combined with other available immunotherapies, might represent a promising strategy in the search for the cure of HIV or other chronic viral infections. FUNDING The CESAR trial was sponsored by IMEA. This work was supported by the NIH (grants UM1AI164562 and R01DK131476).
Collapse
Affiliation(s)
- Federico Perdomo-Celis
- Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, Paris, 75015, France; Institut Pasteur, Université Paris Cité, HIV Inflammation and Persistance Unit, Paris, 75015, France; Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Caroline Passaes
- Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, Paris, 75015, France; Institut Pasteur, Université Paris Cité, HIV Inflammation and Persistance Unit, Paris, 75015, France
| | - Valérie Monceaux
- Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, Paris, 75015, France; Institut Pasteur, Université Paris Cité, HIV Inflammation and Persistance Unit, Paris, 75015, France
| | - Olivier Lambotte
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological, Bacterial Diseases (IMVA-HB/IDMIT/UMRS1184), Le Kremlin Bicêtre, Fontenay aux Roses, France; Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Universitaire Paris Saclay, Service de Médecine interne immunologie clinique, Le Kremlin Bicêtre, France
| | - Dominique Costagliola
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique (IPLESP), Paris, France
| | - Mathieu F Chevalier
- INSERM UMR 1342, Institut de Recherche Saint-Louis (IRSL), Université Paris Cité, Paris, France
| | - Laurence Weiss
- Université de Paris Cité, AP-HP, Paris Centre, Paris, France
| | - Asier Sáez-Cirión
- Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, Paris, 75015, France; Institut Pasteur, Université Paris Cité, HIV Inflammation and Persistance Unit, Paris, 75015, France.
| |
Collapse
|
6
|
Zhou L, Lian G, Zhou T, Cai Z, Yang S, Li W, Cheng L, Ye Y, He M, Lu J, Deng Q, Huang B, Zhou X, Lu D, Zhi F, Cui J. Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity. NATURE CANCER 2025:10.1038/s43018-025-00937-y. [PMID: 40108413 DOI: 10.1038/s43018-025-00937-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 02/27/2025] [Indexed: 03/22/2025]
Abstract
Ferroptosis is closely linked with various pathophysiological processes, including aging, neurodegeneration, ischemia-reperfusion injury, viral infection and, notably, cancer progression; however, its post-translational regulatory mechanisms remain incompletely understood. Here we revealed a crucial role of S-palmitoylation in regulating ferroptosis through glutathione peroxidase 4 (GPX4), a pivotal enzyme that mitigates lipid peroxidation. We identified that zinc finger DHHC-domain containing protein 8 (zDHHC8), an S-acyltransferase that is highly expressed in multiple tumors, palmitoylates GPX4 at Cys75. Through small-molecule drug screening, we identified PF-670462, a zDHHC8-specific inhibitor that promotes the degradation of zDHHC8, consequently attenuating GPX4 palmitoylation and enhancing ferroptosis sensitivity. PF-670462 inhibition of zDHHC8 facilitates the CD8+ cytotoxic T cell-induced ferroptosis of tumor cells, thereby improving the efficacy of cancer immunotherapy in a B16-F10 xenograft model. Our findings reveal the prominent role of the zDHHC8-GPX4 axis in regulating ferroptosis and highlight the potential application of zDHHC8 inhibitors in anticancer therapy.
Collapse
Affiliation(s)
- Liang Zhou
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Guangyu Lian
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Tao Zhou
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Zhe Cai
- Guangzhou Institute of Pediatrics, Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shuai Yang
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Weining Li
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Lilin Cheng
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Ying Ye
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingfeng He
- Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianru Lu
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Qifeng Deng
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China
| | - Bihui Huang
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xiaoqian Zhou
- Department of Gastrointestinal Surgery, The First People's Hospital of Gui Yang, Gui Yang, China
| | - Desheng Lu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Cancer Research Center, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Feng Zhi
- Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Cui
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, Innovation Center of the Sixth Affiliated Hospital, School of Life Sciences of Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
7
|
Kristoff TJ, Evans S, Nayi P, Abousaud M, Goyal S, Liu Y, Shin D, Steuer CE, Saba NF, Schmitt NC. Statin Drugs Are Associated With Response to Immune Checkpoint Blockade in Recurrent/Metastatic Head and Neck Cancer. Cancer Med 2025; 14:e70718. [PMID: 40052634 PMCID: PMC11886884 DOI: 10.1002/cam4.70718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND Statin drugs, frequently used to treat hyperlipidemia, are associated with improved survival outcomes in multiple solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Preclinical studies suggest that manipulation of cholesterol with statins and other agents can enhance the function of multiple components involved in anti-tumor immune responses. Retrospective studies in other solid tumor types suggest that statin therapy is associated with improved responses to immune checkpoint blockade (ICB), but this has not yet been investigated in HNSCC. METHODS Pharmacy records were searched for patients with recurrent/metastatic HNSCC treated at our institution with pembrolizumab or nivolumab from 2015 to 2022. Patients who received less than 3 doses of ICB were excluded. Univariate and multivariate analyses were performed to determine the association between statin use and objective response, progression-free survival (PFS) and overall survival (OS). RESULTS A total of 158 patients were included. Statins were significantly associated with objective response; the strongest associations were seen with rosuvastatin and lovastatin. On multivariate analyses, statins were independently associated with objective response but not with PFS or OS. CONCLUSIONS Statin therapy appears to be an independent predictor of response to ICB in HNSCC. Larger, prospective studies are needed to determine whether specific statin drugs can improve survival outcomes in ICB-treated patients.
Collapse
Affiliation(s)
- Tyler J. Kristoff
- Department of Hematology and Medical OncologyEmory UniversityAtlantaGeorgiaUSA
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
| | - Sean Evans
- Department of Hematology and Medical OncologyEmory UniversityAtlantaGeorgiaUSA
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
| | - Pranay Nayi
- Children's Healthcare of AtlantaAtlantaGeorgiaUSA
| | - Marin Abousaud
- Astellas Pharma Global Development IncNorthbrookIllinoisUSA
| | - Subir Goyal
- Department of Biostatistics and BioinformaticsRollins School of Public Health of Emory UniversityAtlantaGeorgiaUSA
| | - Yuan Liu
- Department of Biostatistics and BioinformaticsRollins School of Public Health of Emory UniversityAtlantaGeorgiaUSA
| | - Dong Shin
- Department of Hematology and Medical OncologyEmory UniversityAtlantaGeorgiaUSA
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
| | - Conor E. Steuer
- Department of Hematology and Medical OncologyEmory UniversityAtlantaGeorgiaUSA
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
| | - Nabil F. Saba
- Department of Hematology and Medical OncologyEmory UniversityAtlantaGeorgiaUSA
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
| | - Nicole C. Schmitt
- Winship Cancer Institute, Emory UniversityAtlantaGeorgiaUSA
- Department of Otolaryngology – Head and Neck SurgeryEmory UniversityAtlantaGeorgiaUSA
| |
Collapse
|
8
|
Kast RE. Potential Benefits of Adding Alendronate, Celecoxib, Itraconazole, Ramelteon, and Simvastatin to Endometrial Cancer Treatment: The EC5 Regimen. Curr Issues Mol Biol 2025; 47:153. [PMID: 40136407 PMCID: PMC11941490 DOI: 10.3390/cimb47030153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/24/2025] [Accepted: 02/24/2025] [Indexed: 03/27/2025] Open
Abstract
Metastatic endometrial cancer continues to be a common cause of death as of 2024, even after maximal use of all currently available standard treatments. To address this problem of metastatic cancer generally in 2025, the drug repurposing movement within oncology identifies medicines in common general medical use that have clinical or preclinical experimental data indicating that they interfere with or inhibit a specific growth driving element identified in a given cancer. The drug repurposing movement within oncology also uses data from large scale in vitro screens of thousands of drugs, looking for simple empirical growth inhibition in a given cancer type. This paper outlines the data showing that five drugs from general medical practice meet these evidence criteria for inhibition of endometrial cancer growth, the EC5 regimen. The EC5 regimen uses the osteoporosis treatment drug, alendronate; the analgesic drug, celecoxib; the antifungal drug, itraconazole; the sleep aid, ramelteon; and the cholesterol lowering drug, simvastatin. Side effects seen with these drugs are usually minimal and easily tolerated by patients.
Collapse
|
9
|
Kumari S, Gupta S, Jamil A, Tabatabaei D, Karakashev S. Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy. J Cell Physiol 2025; 240:e31495. [PMID: 39676338 DOI: 10.1002/jcp.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.
Collapse
Affiliation(s)
- Sangeeta Kumari
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Shraddha Gupta
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Aisha Jamil
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Deyana Tabatabaei
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
| | - Sergey Karakashev
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| |
Collapse
|
10
|
Song Z, Zhou Y, Jiao L, Zhu T, Yu R, Wang Z, Qiu Y, Miao J, Cai T, Zhang S, Liu H, Sun H, Sun Y, Wang D, Liu Z. Lovastatin enhances humoral and cellular immune responses to H1N1 influenza vaccine. Vet Microbiol 2025; 300:110331. [PMID: 39662203 DOI: 10.1016/j.vetmic.2024.110331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/13/2024]
Abstract
The Swine Influenza Virus (SIV) is a major respiratory pathogen in swine, causing acute, febrile, and highly transmissible infections. This virus is widespread globally and poses significant risks to human health and social development. Traditional prevention strategies for SIV rely on the use of inactivated vaccines combined with Alum adjuvants. However, this method is limited by insufficient protection due to the lack of cellular immunity provided by Alum adjuvants. In this study, we investigated the effect of lovastatin, a specific inhibitor of the mevalonate pathway, on the immune response in mice vaccinated with the H1N1 vaccine. We focused on its impact on antibody production, as well as T-cell and B-cell development. Our findings reveal that the combination of lovastatin and H1N1 vaccine (Lov/H1N1) significantly enhances the production of H1N1-specific serum IgG and hemagglutination inhibition (HI) antibodies. Additionally, it promotes T-cell activation in both draining lymph nodes (dLNs) and the spleen. Analysis of cytokines produced after antigenic restimulation of splenic lymphocytes from immunized mice showed that the Lov/H1N1 combination induces both Th1-type (IFNγ, TNFα) and Th2-type (IL4, IL6) responses. Moreover, Lov/H1N1 facilitates the formation of germinal centers (GCs), which are crucial for the generation of memory B cells and long-lived plasma cells. These results indicate that lovastatin is a promising adjuvant candidate, capable of inducing robust cellular and humoral immune responses, thereby overcoming the limitations of Alum adjuvants. Our study provides a foundation for future research on combined vaccine strategies, highlighting Lovastatin's potential to enhance vaccine efficacy through improved immune responses.
Collapse
Affiliation(s)
- Zuchen Song
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yantong Zhou
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Lina Jiao
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Tianyu Zhu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Ruihong Yu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Zheng Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yawei Qiu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Jinfeng Miao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Ting Cai
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315032, PR China
| | - Shun Zhang
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315032, PR China
| | - Huina Liu
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315032, PR China
| | - Haifeng Sun
- Key Laboratory of Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yuechao Sun
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315032, PR China
| | - Deyun Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
| | - Zhenguang Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang 315032, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
| |
Collapse
|
11
|
Rumiano L, Manzo T. Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness. Trends Endocrinol Metab 2024:S1043-2760(24)00321-7. [PMID: 39743401 DOI: 10.1016/j.tem.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/15/2024] [Accepted: 11/27/2024] [Indexed: 01/04/2025]
Abstract
Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.
Collapse
Affiliation(s)
- Letizia Rumiano
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Teresa Manzo
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
| |
Collapse
|
12
|
Covelli V, Buonocore M, Grimaldi M, Scrima M, Santoro A, Marino C, De Simone V, van Baarle L, Biscu F, Scala MC, Sala M, Matteoli G, D'Ursi AM, Rodriquez M. Peptides as modulators of FPPS enzyme: A multifaceted evaluation from the design to the mechanism of action. Eur J Med Chem 2024; 279:116871. [PMID: 39303514 DOI: 10.1016/j.ejmech.2024.116871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/02/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024]
Abstract
Bone diseases are medical conditions caused by the loss of bone homeostasis consecutive to increased osteoclast activity and diminished osteoblast activity. The mevalonate pathway (MVA) is crucial for maintaining this balance since it drives the post-translational prenylation of small guanosine triphosphatases (GTPases) proteins. Farnesyl pyrophosphate synthase (FPPS) plays a crucial role in the MVA pathway. Consequently, in the treatment of bone-related diseases, FPPS is the target of FDA-approved nitrogen-containing bisphosphonates (N-BPs), which have tropism mainly for bone tissue due to their poor penetration in soft tissues. The development of inhibitors targeting the FPPS enzyme has garnered significant interest in recent decades due to FPPS's role in the biosynthesis of cholesterol and other isoprenoids, which are implicated in cancer, bone diseases, and other conditions. In this study, we describe a multidisciplinary approach to designing novel FPPS inhibitors, combining computational modeling, biochemical assays, and biophysical techniques. A series of peptides and phosphopeptides were designed, synthesized, and evaluated for their ability to inhibit FPPS activity. Molecular docking was employed to predict the binding modes of these compounds to FPPS, while Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) spectroscopy experiments - based on Saturation Transfer Difference (STD) and an enzymatic NMR assay - were used to measure their binding affinities and kinetics. The biological activity of the most promising compounds was further assessed in cellular assays using murine colorectal cancer (CRC) cells. Additionally, genomics and metabolomics profiling allowed to unravel the possible mechanisms underlying the activity of the peptides, confirming their involvement in the modulation of the MVA pathway. Our findings demonstrate that the designed peptides and phosphopeptides exhibit significant inhibitory activity against FPPS and possess antiproliferative effects on CRC cells, suggesting their potential as therapeutic agents for cancer.
Collapse
Affiliation(s)
- Verdiana Covelli
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131, Naples, Italy.
| | - Michela Buonocore
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy; Department of Chemical Sciences and Research Centre on Bioactive Peptides (CIRPEB), University of Naples Federico II, Strada Comunale Cintia, 80126, Naples, Italy.
| | - Manuela Grimaldi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Mario Scrima
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Angelo Santoro
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy; Department of Pharmacy, Scuola di Specializzazione in Farmacia Ospedaliera, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Carmen Marino
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Veronica De Simone
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49, 3000, Leuven, Belgium.
| | - Lies van Baarle
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49, 3000, Leuven, Belgium.
| | - Francesca Biscu
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49, 3000, Leuven, Belgium.
| | - Maria Carmina Scala
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Marina Sala
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA)-Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat, 49, 3000, Leuven, Belgium.
| | - Anna Maria D'Ursi
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
| | - Manuela Rodriquez
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131, Naples, Italy.
| |
Collapse
|
13
|
Osataphan S, Awidi M, Jan YJ, Gunturu K, Sundararaman S, Viray H, Frankenberger E, Mariano M, O'Loughlin L, Piper-Vallillo A, Stafford K, Kolnick A, Ghazalah H, Sehgal K, Patti ME, Costa D, Lam P, Rangachari D. Association between higher glucose levels and reduced survival in patients with non-small cell lung cancer treated with immune checkpoint inhibitors. Lung Cancer 2024; 198:108023. [PMID: 39571252 DOI: 10.1016/j.lungcan.2024.108023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/29/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Obesity and hypercholesterolemia have been associated with better responses to ICIs in NSCLC, while type 2 diabetes (T2D) has been associated with a worse response. However, the association between glucose levels and outcomes remains unknown. This study investigated the impact of mean baseline glucose levels, T2D, dyslipidemia, and obesity on overall survival (OS) in NSCLC patients undergoing ICI therapy. METHODS A multicenter retrospective cohort study was conducted using data from three medical centers, with locally advanced or metastatic NSCLC patients receiving ICI, regardless of treatment line or concurrent therapy. Random venous glucose levels within 4 weeks prior to ICI initiation, BMI, history of dyslipidemia, and T2D, along with OS, were assessed. Patients with BMI < 18.5 were excluded. RESULTS Among 438 patients, those with the highest quartile of baseline glucose levels had significantly shorter OS compared to those in the lowest quartile (HR, 1.53; 95 % CI, 1.08 - 2.15; p-value = 0.016). This association remind consistent after adjusting for steroid use, diabetes, performance status and glucose-lowering medication use. These effects were consistently observed in subsets of patients treated with ICI monotherapy and with PD-L1 TPS ≥ 1 %. CONCLUSION Higher mean baseline glucose levels correlated with shorter survival in patients with NSCLC treated with ICIs. The divergent effects of individual metabolic syndrome components on ICI response in patients with NSCLC underscore the complexity of metabolic influences on treatment outcomes.
Collapse
Affiliation(s)
- Soravis Osataphan
- Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Muhammad Awidi
- Lahey Hospital & Medical Center, Burlington, MA, United States; Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Yu Jen Jan
- Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States; Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Krishna Gunturu
- Lahey Hospital & Medical Center, Burlington, MA, United States; Hartford HealthCare Cancer Institute, Hartford, CT, United States
| | - Shriram Sundararaman
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Hollis Viray
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | | | - Melissa Mariano
- Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Lauren O'Loughlin
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | | | - Katherine Stafford
- Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States; Denver Health & Hospital Authority, Denver, CO, United States
| | | | - Hind Ghazalah
- Lahey Hospital & Medical Center, Burlington, MA, United States
| | - Kartik Sehgal
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States; Brigham and Women's Hospital, Boston, MA, United States
| | | | - Daniel Costa
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Prudence Lam
- Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Deepa Rangachari
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
| |
Collapse
|
14
|
Zhen W, Germanas T, Weichselbaum RR, Lin W. Multifunctional Nanomaterials Mediate Cholesterol Depletion for Cancer Treatment. Angew Chem Int Ed Engl 2024; 63:e202412844. [PMID: 39146242 PMCID: PMC11534517 DOI: 10.1002/anie.202412844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/02/2024] [Accepted: 08/14/2024] [Indexed: 08/17/2024]
Abstract
Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.
Collapse
Affiliation(s)
- Wenyao Zhen
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Tomas Germanas
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
| | - Wenbin Lin
- Department of Chemistry, The University of Chicago, Chicago, Illinois, 60637, United States
- Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois, 60637, United States
| |
Collapse
|
15
|
Miao W, Song Z, Jiao L, Yu R, Wang D, Jin L, Ge X, Zhou Y, Wang Z, Han L, He J, Sun H, Sun X, Zhang A, Zhang L, Liu Z. Enhancing Vaccine Efficacy with Polyethylenimine-Modified Lovastatin-Loaded Nanoparticle Pickering Emulsion Adjuvant. Mol Pharm 2024; 21:5807-5817. [PMID: 39432317 DOI: 10.1021/acs.molpharmaceut.4c00828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Despite the potent immunoadjuvant properties of mevalonate pathway inhibitors, their application is constrained by poor solubility and instability. In this study, we developed a cationic nanoparticle-stabilized Pickering emulsion loaded with lovastatin (Lov-PPE), using polyethylenimine (PEI)-modified PLGA nanoparticles and squalene as carriers. The system was prepared and tested by evaluating the physicochemical properties and adjuvant efficacy of the Lov-PPE. Lov-PPE/O demonstrated good particle size distribution and zeta potential, with an adsorption efficiency of up to 73.07%. The immunization results showed that Lov-PPE/O significantly promoted the production of OVA-specific IgG antibodies, activated CD4+ and CD8+ T cells, and induced a strong mixed Th1/2 immune response. Additionally, safety assessments indicated that Lov-PPE/O has good in vivo safety. This study demonstrates that the PEI-modified lovastatin PLGA nanoparticle Pickering emulsion (Lov-PPE) is an effective vaccine adjuvant capable of significantly enhancing humoral and cellular immune responses while possessing good safety, offering a new strategy for vaccine formulation development.
Collapse
Affiliation(s)
- Wei Miao
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Zuchen Song
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Lina Jiao
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Ruihong Yu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Deyun Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Lan Jin
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Xincheng Ge
- Linyi Agricultural Technology Extension Center, Shandong 276000, P.R. China
| | - Yantong Zhou
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Zheng Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Linjun Han
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
| | - Jing He
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
| | - Haifeng Sun
- Key Laboratory of Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| | - Xiaoxuan Sun
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
| | - Aqin Zhang
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
| | - Li Zhang
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu 225300, China
| | - Zhenguang Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P.R. China
| |
Collapse
|
16
|
Qin Z, Xie H, Su P, Song Z, Xu R, Guo S, Fu Y, Zhang P, Jiang H. Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis. Clin Transl Med 2024; 14:e70082. [PMID: 39521624 PMCID: PMC11550091 DOI: 10.1002/ctm2.70082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/13/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Bisphosphonates (BPs) are the first-line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs-related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear. METHODS The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing Lyve1creERT; SIRT6f/f and Lyve1creERT; ATG5f/f mice, we evaluated the role of ERS-induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle-loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ. RESULTS The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ERS and the inhibition of autophagy in LECs, ultimately leading to apoptosis. Mechanistically, ZA activated XBP1s through the NAD+/SIRT6 pathway, initiating ERS-induced apoptosis in LECs. The conditional knockout mouse models demonstrated that the deletion of SIRT6 or ATG5 significantly worsened lymphatic drainage and inflammatory infiltration in BRONJ. Additionally, the innovative nanoparticle ZDPR alleviated ERS-apoptosis in LECs and enhanced lymphatic function, facilitating inflammation resolution. CONCLUSION Our study has elucidated the role of the NAD+/SIRT6/XBP1s pathway in ERS-induced apoptosis in ZA-treated LECs, and further confirmed the therapeutic potential of ZDPR in restoring endothelial function and improving lymphatic drainage, thereby effectively mitigating BRONJ. KEY POINTS Bisphosphonate-induced lymphatic drainage impairment exacerbates bone necrosis. Zoledronate acid triggers endoplasmic reticulum stress and apoptosis in lymphatic endothelial cells via the NAD+/SIRT6/XBP1s pathway. Novel nanoparticle-loaded Zoledronate acid and rapamycin enhances autophagy, restores lymphatic function, and mitigates bisphosphonates-related osteonecrosis of the jaw progression.
Collapse
Affiliation(s)
- Ziyue Qin
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Hanyu Xie
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Pengcheng Su
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Zesheng Song
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Rongyao Xu
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Songsong Guo
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Yu Fu
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Ping Zhang
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
| | - Hongbing Jiang
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of StomatologyNanjing Medical UniversityNanjingChina
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral DiseasesNanjing Medical UniversityNanjingJiangsuChina
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityNanjingJiangsuChina
| |
Collapse
|
17
|
Tang Y, Chen Z, Zuo Q, Kang Y. Regulation of CD8+ T cells by lipid metabolism in cancer progression. Cell Mol Immunol 2024; 21:1215-1230. [PMID: 39402302 PMCID: PMC11527989 DOI: 10.1038/s41423-024-01224-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/22/2024] [Indexed: 11/02/2024] Open
Abstract
Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.
Collapse
Affiliation(s)
- Yong Tang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Ziqing Chen
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Qianying Zuo
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA.
- Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
| |
Collapse
|
18
|
Zhang X, Chen Y, Sun G, Fei Y, Zhu H, Liu Y, Dan J, Li C, Cao X, Liu J. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling. Nat Metab 2024; 6:2118-2137. [PMID: 39425002 DOI: 10.1038/s42255-024-01149-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 09/24/2024] [Indexed: 10/21/2024]
Abstract
Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.
Collapse
Affiliation(s)
- Xiaomin Zhang
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yali Chen
- Department of Immunology, Institute of Basic Medical Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Geng Sun
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yankang Fei
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Ha Zhu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yanfang Liu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Junyan Dan
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Chunzhen Li
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Xuetao Cao
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
- Department of Immunology, Institute of Basic Medical Research, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, China
| | - Juan Liu
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China.
| |
Collapse
|
19
|
Zhang M, Kang N, Yu X, Zhang X, Duan Q, Ma X, Zhao Q, Wang Z, Wang X, Liu Y, Zhang Y, Zhu C, Gao R, Min X, Li C, Jin J, Cao Q, Liu R, Bai X, Yang H, Zhao L, Liu J, Chen H, Zhang Y, Liu W, Zheng W. TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet's disease. Nat Commun 2024; 15:9261. [PMID: 39461948 PMCID: PMC11513106 DOI: 10.1038/s41467-024-53528-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet's disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.
Collapse
Affiliation(s)
- Menghao Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Na Kang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xin Yu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Xiaoyang Zhang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Qinghui Duan
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xianqiang Ma
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China
| | - Qiancheng Zhao
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China
| | - Zhimian Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Xiao'ou Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Yeling Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Yuxiao Zhang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Can Zhu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Ruiyu Gao
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Xin Min
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Cuifeng Li
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Jin Jin
- Center for Neuroimmunology and Health Longevity, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qian Cao
- Department of gastroenterology & Inflammatory bowel disease Center, Sir Run Run Shaw hospital, school of medicine, Zhejiang University, Hangzhou, China
| | - Rongbei Liu
- Department of gastroenterology & Inflammatory bowel disease Center, Sir Run Run Shaw hospital, school of medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyin Bai
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Jinjing Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China
| | - Yonghui Zhang
- School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China
| | - Wanli Liu
- State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Tsinghua Changgung Hospital, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
| | - Wenjie Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, The Ministry of Education Key Laboratory, Beijing, China.
| |
Collapse
|
20
|
Yang H, Huang R, Zhang P, Liu Y, Liu Z, He J, Peng X. Association between statin use and immune-related adverse events in patients treated with immune checkpoint inhibitors: analysis of the FAERS database. Front Immunol 2024; 15:1439231. [PMID: 39439792 PMCID: PMC11493589 DOI: 10.3389/fimmu.2024.1439231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
Background Understanding the risk relationship between statin use and immune-related adverse events (irAEs) in patients undergoing immune checkpoint inhibitors (ICIs) therapy is crucial for optimizing oncological management. Objective This study aimed to investigate whether the use of statins increases the risk of irAEs in patients receiving ICI therapy. Methods This study primarily utilized data from FAERS database. Multivariable logistic regression was the principal method of analysis, and the Benjamini-Hochberg procedure was employed to adjust for multiple hypothesis testing. Results In a group of 145,214 patients undergoing ICI therapy, 9,339 reported using statin medications. Multivariable analysis indicated an increased risk of irAEs among statin users (OR 1.199, 95% CI: 1.141-1.261; FDR p < 0.001) in comparison to those not using statins. Notably, increased risks were observed particularly in patients diagnosed with lung, pancreatic, and renal cancers. The link between statin usage and increased irAEs risk remained consistent across various ICIs treatments. Conclusions Statin medication usage is linked to an elevated probability of experiencing irAEs in patients enrolled in ICI therapy. In cancer patients receiving immune checkpoint inhibitors, careful consideration of statin use is essential to avoid potentially increased irAEs risk. These findings provide critical guidance for clinicians in developing treatment strategies that balance therapeutic efficacy and safety in oncological management.
Collapse
Affiliation(s)
- Huaju Yang
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rendong Huang
- Hangzhou Linan Guorui Health Industry Investment Co., Ltd, Hangzhou, Zhejiang, China
| | - Ping Zhang
- Department of Oncology, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu First People’s Hospital, Chengdu, Sichuan, China
| | - Yingtong Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zheran Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiagang He
- Department of Medical Education, Kweichow Moutai Hospital, Zunyi, Guizhou, China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
21
|
Ye X, Liu Y, Wei L, Sun Y, Zhang X, Wang H, Guo H, Qin X, Li X, Qu D, Huo J, Chen Y. Monocyte/Macrophage-Mediated Transport of Dual-Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein-1 Inhibitor Against Microsatellite-Stable Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405886. [PMID: 39101234 PMCID: PMC11481235 DOI: 10.1002/advs.202405886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/08/2024] [Indexed: 08/06/2024]
Abstract
Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.
Collapse
Affiliation(s)
- Xietao Ye
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Yuping Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
- Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese MedicineNanjing210028China
| | - Liangyin Wei
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Yeyang Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Xiaoran Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Hong Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Hong Guo
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Xiaoying Qin
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Xiaoqi Li
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Ding Qu
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
| | - Jiege Huo
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese MedicineNanjing210028China
| | - Yan Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210028China
- Multi‐component of Traditional Chinese Medicine and Microecology Research CenterJiangsu Province Academy of Traditional Chinese MedicineNanjing210028China
- Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese MedicineNanjing210028China
| |
Collapse
|
22
|
Jiang R, Lou L, Shi W, Chen Y, Fu Z, Liu S, Sok T, Li Z, Zhang X, Yang J. Statins in Mitigating Anticancer Treatment-Related Cardiovascular Disease. Int J Mol Sci 2024; 25:10177. [PMID: 39337662 PMCID: PMC11432657 DOI: 10.3390/ijms251810177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/14/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment.
Collapse
Affiliation(s)
- Rong Jiang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lian Lou
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Wen Shi
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yuxiao Chen
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhaoming Fu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shuo Liu
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Thida Sok
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhihang Li
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xuan Zhang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Yang
- Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| |
Collapse
|
23
|
Michael R, Ranjan A, Gautam S, Trivedi PK. HY5 and PIF antagonistically regulate HMGR expression and sterol biosynthesis in Arabidopsis thaliana. PLANT SCIENCE : AN INTERNATIONAL JOURNAL OF EXPERIMENTAL PLANT BIOLOGY 2024; 346:112168. [PMID: 38914157 DOI: 10.1016/j.plantsci.2024.112168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 06/08/2024] [Accepted: 06/18/2024] [Indexed: 06/26/2024]
Abstract
Secondary metabolites play multiple crucial roles in plants by modulating various regulatory networks. The biosynthesis of these compounds is unique to each species and is intricately controlled by a range of developmental and environmental factors. While light's role in certain secondary metabolites is evident, its impact on sterol biosynthesis remains unclear. Previous studies indicate that ELONGATED HYPOCOTYL5 (HY5), a bZIP transcription factor, is pivotal in skotomorphogenesis to photomorphogenesis transition. Additionally, PHYTOCHROME INTERACTING FACTORs (PIFs), bHLH transcription factors, act as negative regulators. To unveil the light-dependent regulation of the mevalonic acid (MVA) pathway, a precursor for sterol biosynthesis, mutants of light signaling components, specifically hy5-215 and the pifq quadruple mutant (pif 1,3,4, and 5), were analyzed in Arabidopsis thaliana. Gene expression analysis in wild-type and mutants implicates HY5 and PIFs in regulating sterol biosynthesis genes. DNA-protein interaction analysis confirms their interaction with key genes like AtHMGR2 in the rate-limiting pathway. Results strongly suggest HY5 and PIFs' pivotal role in light-dependent MVA pathway regulation, including the sterol biosynthetic branch, in Arabidopsis, highlighting a diverse array of light signaling components finely tuning crucial growth pathways.
Collapse
Affiliation(s)
- Rahul Michael
- CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research (AcSIR), CSIR, Ghaziabad 201002, India
| | - Avriti Ranjan
- Academy of Scientific and Innovative Research (AcSIR), CSIR, Ghaziabad 201002, India; Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Picnic Spot Road, Lucknow 226015, India
| | - Swati Gautam
- CSIR-National Botanical Research Institute (CSIR-NBRI), Rana Pratap Marg, Lucknow 226001, India; Academy of Scientific and Innovative Research (AcSIR), CSIR, Ghaziabad 201002, India
| | - Prabodh Kumar Trivedi
- Academy of Scientific and Innovative Research (AcSIR), CSIR, Ghaziabad 201002, India; Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Picnic Spot Road, Lucknow 226015, India.
| |
Collapse
|
24
|
Song Z, Jiao L, Wang D, Qiu Y, Miao J, Zhu T, Yu R, Wang Z, Zhou Y, Cai T, Zhang S, Liu H, Sun H, Sun Y, Liu Z. Controlling the speed of antigens transport in dendritic cells improves humoral and cellular immunity for vaccine. Biomed Pharmacother 2024; 177:117036. [PMID: 38941888 DOI: 10.1016/j.biopha.2024.117036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 06/30/2024] Open
Abstract
Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.
Collapse
Affiliation(s)
- Zuchen Song
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Lina Jiao
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Deyun Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Yawei Qiu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Jinfeng Miao
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Tianyu Zhu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Ruihong Yu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Zheng Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Yantong Zhou
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Ting Cai
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China
| | - Shun Zhang
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China
| | - Huina Liu
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China
| | - Haifeng Sun
- Key Laboratory of Bacteriology, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China
| | - Yuechao Sun
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China
| | - Zhenguang Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, PR China.
| |
Collapse
|
25
|
Park JH, Mortaja M, Son HG, Zhao X, Sloat LM, Azin M, Wang J, Collier MR, Tummala KS, Mandinova A, Bardeesy N, Semenov YR, Mino-Kenudson M, Demehri S. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat Commun 2024; 15:4099. [PMID: 38816352 PMCID: PMC11139893 DOI: 10.1038/s41467-024-48441-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
Collapse
Affiliation(s)
- Jong Ho Park
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea
| | - Mahsa Mortaja
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Heehwa G Son
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Xutu Zhao
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lauren M Sloat
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marjan Azin
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jun Wang
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael R Collier
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Krishna S Tummala
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA
| | - Anna Mandinova
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nabeel Bardeesy
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Yevgeniy R Semenov
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
26
|
Guo H, Ding X, Hua D, Liu M, Yang M, Gong Y, Ye N, Chen X, He J, Zhang Y, Xu X, Li J. Enhancing Dengue Virus Production and Immunogenicity with Celcradle™ Bioreactor: A Comparative Study with Traditional Cell Culture Methods. Vaccines (Basel) 2024; 12:563. [PMID: 38932292 PMCID: PMC11209354 DOI: 10.3390/vaccines12060563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/12/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024] Open
Abstract
The dengue virus, the primary cause of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is the most widespread mosquito-borne virus worldwide. In recent decades, the prevalence of dengue fever has increased markedly, presenting substantial public health challenges. Consequently, the development of an efficacious vaccine against dengue remains a critical goal for mitigating its spread. Our research utilized Celcradle™, an innovative tidal bioreactor optimized for high-density cell cultures, to grow Vero cells for dengue virus production. By maintaining optimal pH levels (7.0 to 7.4) and glucose concentrations (1.5 g/L to 3.5 g/L) during the proliferation of cells and viruses, we achieved a peak Vero cell count of approximately 2.46 × 109, nearly ten times the initial count. The use of Celcradle™ substantially decreased the time required for cell yield and virus production compared to conventional Petri dish methods. Moreover, our evaluation of the immunogenicity of the Celcradle™-produced inactivated DENV4 through immunization of mice revealed that sera from these mice demonstrated cross-reactivity with DENV4 cultured in Petri dishes and showed elevated antibody titers compared to those from mice immunized with virus from Petri dishes. These results indicate that the dengue virus cultivated using the Celcradle™ system exhibited enhanced immunogenicity relative to that produced in traditional methods. In conclusion, our study highlights the potential of the Celcradle™ bioreactor for large-scale production of inactivated dengue virus vaccines, offering significant promise for reducing the global impact of dengue virus infections and accelerating the development of effective vaccination strategies.
Collapse
Affiliation(s)
- Hongxia Guo
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Xiaoyan Ding
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
- Department of Pediatrics, Ludwig-Maximilians University of Munich, 80337 Munich, Germany
| | - Dong Hua
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Minchi Liu
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Maocheng Yang
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Yuanxin Gong
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Nan Ye
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Xiaozhong Chen
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Jiuxiang He
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Yu Zhang
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Xiaofeng Xu
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| | - Jintao Li
- Department of Biosafety, School of Basic Medicine, Army Medical University, Chongqing 400038, China; (H.G.); (X.D.); (D.H.); (M.L.); (M.Y.); (Y.G.); (N.Y.); (X.C.); (J.H.); (Y.Z.); (X.X.)
| |
Collapse
|
27
|
Chapman NM, Chi H. Metabolic rewiring and communication in cancer immunity. Cell Chem Biol 2024; 31:862-883. [PMID: 38428418 PMCID: PMC11177544 DOI: 10.1016/j.chembiol.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/29/2024] [Accepted: 02/08/2024] [Indexed: 03/03/2024]
Abstract
The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.
Collapse
Affiliation(s)
- Nicole M Chapman
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
| |
Collapse
|
28
|
Ucche S, Hayakawa Y. Immunological Aspects of Cancer Cell Metabolism. Int J Mol Sci 2024; 25:5288. [PMID: 38791327 PMCID: PMC11120853 DOI: 10.3390/ijms25105288] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.
Collapse
Affiliation(s)
- Sisca Ucche
- Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan;
- Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Yoshihiro Hayakawa
- Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan;
| |
Collapse
|
29
|
Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, Beasley GM, Theivanthiran B, Hanks BA. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol 2024; 9:eadi4191. [PMID: 38728412 PMCID: PMC11926670 DOI: 10.1126/sciimmunol.adi4191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 04/12/2024] [Indexed: 05/12/2024]
Abstract
Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.
Collapse
Affiliation(s)
- Michael P. Plebanek
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Yue Xue
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Y-Van Nguyen
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Nicholas C. DeVito
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Xueying Wang
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| | - Alisha Holtzhausen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Georgia M. Beasley
- Department of Surgery, Division of Surgical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Balamayooran Theivanthiran
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Brent A. Hanks
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| |
Collapse
|
30
|
McKechnie T, Brown Z, Lovrics O, Yang S, Kazi T, Eskicioglu C, Parvez E. Concurrent Use of Statins in Patients Undergoing Curative Intent Treatment for Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis. Clin Breast Cancer 2024; 24:e103-e115. [PMID: 38296737 DOI: 10.1016/j.clbc.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 02/02/2024]
Abstract
Pre-clinical studies in triple negative breast cancer (TNBC) suggest that statins may inhibit cell proliferation, promote cell-cycle arrest, induce apoptosis, change the tumor microenvironment, and improve effectiveness of other therapies. Observational studies have demonstrated variable effects from statin therapy on oncologic outcomes in these patients. As such, we aimed to pool previous data via a systematic review and meta-analysis to elucidate the impact of concurrent statin use on oncologic outcomes for patients with TNBC. Medline, EMBASE, CENTRAL, and PubMed were systematically searched from inception through to June 2022. Studies were included if they compared patients with TNBC receiving and not receiving statin therapy concurrently with oncologic treatment for curative intent in terms of recurrence and survival in a non-metastatic setting. The primary outcomes were 5-year disease-free survival (DFS) and 5-year overall survival (OS). A pairwise meta-analyses was performed using inverse variance random effects. Risk of bias was assessed with the ROBINS-I and the GRADE approach was conducted to assess quality of evidence. From 4014 citations, 5 studies with 625 patients on statin therapy and 2707 patients not on statin therapy were included. There was a significant increase in 5-year DFS for patients on statin therapy compared to patients not on statin therapy (OR 1.44, 95% CI 1.04-1.98, P = .03). No significant difference was noted in 5-year OS between the 2 groups (OR 1.12, 95% CI 0.86-1.47, P = .40). Included studies were at moderate-to-high risk of bias. The GRADE quality of evidence was very low. This review presents very low-quality evidence that concurrent use of statins with oncologic treatment may potentially improve long-term DFS for patients with TNBC undergoing curative intent therapy. Future research by way of large, prospective study is required to further clarify the clinical utility of statins on patients undergoing treatment for TNBC.
Collapse
Affiliation(s)
- Tyler McKechnie
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Zachary Brown
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Olivia Lovrics
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Shuling Yang
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Tania Kazi
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Cagla Eskicioglu
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada; Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Elena Parvez
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada; Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
| |
Collapse
|
31
|
Li K, Zhang J, Lyu H, Yang J, Wei W, Wang Y, Luo H, Zhang Y, Jiang X, Yi H, Wang M, Zhang C, Wu K, Xiao L, Wen W, Xu H, Li G, Wan Y, Yang F, Yang R, Fu X, Qin B, Zhou Z, Zhang H, Lee M. CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306827. [PMID: 38308184 PMCID: PMC11005689 DOI: 10.1002/advs.202306827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/15/2024] [Indexed: 02/04/2024]
Abstract
Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.
Collapse
|
32
|
Gupta A, Das D, Taneja R. Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors. Cancers (Basel) 2024; 16:1313. [PMID: 38610991 PMCID: PMC11010992 DOI: 10.3390/cancers16071313] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.
Collapse
Affiliation(s)
| | | | - Reshma Taneja
- Department of Physiology, Healthy Longevity and NUS Centre for Cancer Research Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore 117593, Singapore
| |
Collapse
|
33
|
Zhang Y, Song Z, Zhang Z, Zhang T, Gu P, Feng Z, Xu S, Yang Y, Wang D, Liu Z. Preparation and characterization of pickering emulsion stabilized by lovastatin nanoparticles for vaccine adjuvants. Int J Pharm 2024; 653:123901. [PMID: 38368969 DOI: 10.1016/j.ijpharm.2024.123901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/11/2024] [Accepted: 02/08/2024] [Indexed: 02/20/2024]
Abstract
While research on mevalonate inhibitors as vaccine adjuvants has made great progress to enhance the effectiveness of the vaccine, co delivery of lovastatin and antigens (OVA) remains an enormous challenge. Here, we encapsulated lovastatin into PLGA nanoparticles. PLGA loading lovastatin was further emulsified with squalene to prepare Pickering emulsion. The emulsification conditions of Pickering emulsion were optimized, and the optimal preparation conditions were obtained. After loading lovastatin and OVA, the size and zeta potential of LS-PPAS/OVA was 1043.33 nm and -22.07 mv, the adsorption rate of OVA was 63.34 %. The adsorbing of LS-PLGA nanoparticles on the surface of squalene in Pickering emulsions was demonstrated by Fluorescent confocal microscopy. After immunization, LS-PPAS enhanced the activation of dendritic cells in lymph nodes, further study found LS-PPAS not only elicited elevated levels of OVA-specific IgG and its subtypes, but also promoted the secretion of TNF-α, IFN-γ, and IL-6 in serum as a marker of cellular immunity. Importantly, LS-PPAS showed sufficient security through monitoring levels of biochemical parameters in serum and pathological observation of organ following vaccinations. LS-PPAS may act as a promising vaccine carrier to produce strong humoral and cellular immunity with acceptable safety.
Collapse
Affiliation(s)
- Yue Zhang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Zuchen Song
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Zhimin Zhang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Tao Zhang
- Beijing Key Laboratory of Traditional Chinese Veterinary Medicine, Beijing University of Agriculture, Beijing 102206, PR China
| | - Pengfei Gu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Zian Feng
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Shuwen Xu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Yang Yang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Deyun Wang
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China
| | - Zhenguang Liu
- Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
| |
Collapse
|
34
|
Li C, Li J, Sun P, Li T, Yan X, Ye J, Wu J, Zhu L, Wang H, Pan C. Production of Promising Heat-Labile Enterotoxin (LT) B Subunit-Based Self-Assembled Bioconjugate Nanovaccines against Infectious Diseases. Vaccines (Basel) 2024; 12:347. [PMID: 38675730 PMCID: PMC11054625 DOI: 10.3390/vaccines12040347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/15/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Nanoparticles (NPs) have been widely utilized in vaccine design. Although numerous NPs have been explored, NPs with adjuvant effects on their own have rarely been reported. We produce a promising self-assembled NP by integrating the pentameric Escherichia coli heat-labile enterotoxin B subunit (LTB) (studied as a vaccine adjuvant) with a trimer-forming peptide. This fusion protein can self-assemble into the NP during expression, and polysaccharide antigens (OPS) are then loaded in vivo using glycosylation. We initially produced two Salmonella paratyphi A conjugate nanovaccines using two LTB subfamilies (LTIB and LTIIbB). After confirming their biosafety in mice, the data showed that both nanovaccines (NP(LTIB)-OPSSPA and NP(LTIIbB)-OPSSPA) elicited strong polysaccharide-specific antibody responses, and NP(LTIB)-OPS resulted in better protection. Furthermore, polysaccharides derived from Shigella or Klebsiella pneumoniae were loaded onto NP(LTIB) and NP(LTIIbB). The animal experimental results indicated that LTIB, as a pentamer module, exhibited excellent protection against lethal infections. This effect was also consistent with that of the reported cholera toxin B subunit (CTB) modular NP in all three models. For the first time, we prepared a novel promising self-assembled NP based on LTIB. In summary, these results indicated that the LTB-based nanocarriers have the potential for broad applications, further expanding the library of self-assembled nanocarriers.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Hengliang Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100071, China; (C.L.); (J.L.); (P.S.); (T.L.); (X.Y.); (J.Y.); (L.Z.)
| | - Chao Pan
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100071, China; (C.L.); (J.L.); (P.S.); (T.L.); (X.Y.); (J.Y.); (L.Z.)
| |
Collapse
|
35
|
Ju SH, Lim JY, Song M, Kim JM, Kang YE, Yi HS, Joung KH, Lee JH, Kim HJ, Ku BJ. Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial. Front Endocrinol (Lausanne) 2024; 15:1336357. [PMID: 38586464 PMCID: PMC10996898 DOI: 10.3389/fendo.2024.1336357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/04/2024] [Indexed: 04/09/2024] Open
Abstract
Objectives Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers. Methods In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication. Results The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339). Conclusions We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.
Collapse
Affiliation(s)
- Sang-Hyeon Ju
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Joung Youl Lim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Minchul Song
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Ji Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Yea Eun Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Hyon-Seung Yi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Kyong Hye Joung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Ju Hee Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Hyun Jin Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Bon Jeong Ku
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| |
Collapse
|
36
|
Terzoli S, Marzano P, Cazzetta V, Piazza R, Sandrock I, Ravens S, Tan L, Prinz I, Balin S, Calvi M, Carletti A, Cancellara A, Coianiz N, Franzese S, Frigo A, Voza A, Calcaterra F, Di Vito C, Della Bella S, Mikulak J, Mavilio D. Expansion of memory Vδ2 T cells following SARS-CoV-2 vaccination revealed by temporal single-cell transcriptomics. NPJ Vaccines 2024; 9:63. [PMID: 38509155 PMCID: PMC10954735 DOI: 10.1038/s41541-024-00853-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/05/2024] [Indexed: 03/22/2024] Open
Abstract
γδ T cells provide rapid cellular immunity against pathogens. Here, we conducted matched single-cell RNA-sequencing and γδ-TCR-sequencing to delineate the molecular changes in γδ T cells during a longitudinal study following mRNA SARS-CoV-2 vaccination. While the first dose of vaccine primes Vδ2 T cells, it is the second administration that significantly boosts their immune response. Specifically, the second vaccination uncovers memory features of Vδ2 T cells, shaped by the induction of AP-1 family transcription factors and characterized by a convergent central memory signature, clonal expansion, and an enhanced effector potential. This temporally distinct effector response of Vδ2 T cells was also confirmed in vitro upon stimulation with SARS-CoV-2 spike-peptides. Indeed, the second challenge triggers a significantly higher production of IFNγ by Vδ2 T cells. Collectively, our findings suggest that mRNA SARS-CoV-2 vaccination might benefit from the establishment of long-lasting central memory Vδ2 T cells to confer protection against SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Sara Terzoli
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
| | - Paolo Marzano
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Inga Sandrock
- Institute of Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Sarina Ravens
- Institute of Immunology, Hannover Medical School (MHH), Hannover, Germany
| | - Likai Tan
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School (MHH), Hannover, Germany
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simone Balin
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Michela Calvi
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Anna Carletti
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Assunta Cancellara
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Nicolò Coianiz
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Sara Franzese
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Alessandro Frigo
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Antonio Voza
- Department of Biomedical Sciences, Humanitas University, Milan, Pieve Emanuele, Italy
- Department of Biomedical Unit, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Francesca Calcaterra
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Clara Di Vito
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
| | - Silvia Della Bella
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy.
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Rozzano, Italy.
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
| |
Collapse
|
37
|
Zhang X, Wei M, Zhang Z, Zeng Y, Zou F, Zhang S, Wang Z, Chen F, Xiong H, Li Y, Zhou L, Li T, Zheng Q, Yu H, Zhang J, Gu Y, Zhao Q, Li S, Xia N. Risedronate-functionalized manganese-hydroxyapatite amorphous particles: A potent adjuvant for subunit vaccines and cancer immunotherapy. J Control Release 2024; 367:13-26. [PMID: 38244843 DOI: 10.1016/j.jconrel.2024.01.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 01/22/2024]
Abstract
The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes.
Collapse
Affiliation(s)
- Xiuli Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Mingjing Wei
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Zhigang Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Yarong Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Feihong Zou
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Sibo Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Zhiping Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Fentian Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Hualong Xiong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Yufang Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Lizhi Zhou
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Tingting Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Qingbing Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Hai Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Ying Gu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
| | - Shaowei Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China.
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, Collaborative Innovation Center of Biologic Products, Xiamen University, Xiamen 361102, China.
| |
Collapse
|
38
|
Li M, Jiang A, Han H, Chen M, Wang B, Cheng Y, Zhang H, Wang X, Dai W, Yang W, Zhang Q, He B. A Trinity Nano-Vaccine System with Spatiotemporal Immune Effect for the Adjuvant Cancer Therapy after Radiofrequency Ablation. ACS NANO 2024; 18:4590-4612. [PMID: 38047809 DOI: 10.1021/acsnano.3c03352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Cancer vaccine gains great attention with the advances in tumor immunology and nanotechnology, but its long-term efficacy is restricted by the unsustainable immune activity after vaccination. Here, we demonstrate the vaccine efficacy is negatively correlated with the tumor burden. To maximum the vaccine-induced immunity and prolong the time-effectiveness, we design a priming-boosting vaccination strategy by combining with radiofrequency ablation (RFA), and construct a bisphosphonate nanovaccine (BNV) system. BNV system consists of nanoparticulated bisphosphonates with dual electric potentials (BNV(+&-)), where bisphosphonates act as the immune adjuvant by blocking mevalonate metabolism. BNV(+&-) exhibits the spatial and temporal heterogeneity in lymphatic delivery and immune activity. As the independent components of BNV(+&-), BNV(-) is drained to the lymph nodes, and BNV(+) is retained at the injection site. The alternately induced immune responses extend the time-effectiveness of antitumor immunity and suppress the recurrence and metastasis of colorectal cancer liver metastases after RFA. As a result, this trinity system integrated with RFA therapy, bisphosphonate adjuvant, and spatiotemporal immune effect provides an orientation for the sustainable regulation and precise delivery of cancer vaccines.
Collapse
Affiliation(s)
- Minghui Li
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Anna Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100191, China
| | - Huize Han
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Meifang Chen
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Bing Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100191, China
| | - Yuxi Cheng
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hua Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xueqing Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Wenbing Dai
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Wei Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing 100191, China
| | - Qiang Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Bing He
- Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| |
Collapse
|
39
|
Jo W, Won T, Daoud A, Čiháková D. Immune checkpoint inhibitors associated cardiovascular immune-related adverse events. Front Immunol 2024; 15:1340373. [PMID: 38375475 PMCID: PMC10875074 DOI: 10.3389/fimmu.2024.1340373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications.
Collapse
Affiliation(s)
- Wonyoung Jo
- Department of Biomedical Engineering, Johns Hopkins University, Whiting School of Engineering, Baltimore, MD, United States
| | - Taejoon Won
- Department of Pathobiology, University of Illinois Urbana-Champaign, College of Veterinary Medicine, Urbana, IL, United States
| | - Abdel Daoud
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
| | - Daniela Čiháková
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
| |
Collapse
|
40
|
Adhikary K, Banerjee P, Barman S, Bandyopadhyay B, Bagchi D. Nutritional Aspects, Chemistry Profile, Extraction Techniques of Lemongrass Essential Oil and It's Physiological Benefits. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2024; 43:183-200. [PMID: 37579058 DOI: 10.1080/27697061.2023.2245435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/01/2023] [Accepted: 08/02/2023] [Indexed: 08/16/2023]
Abstract
Lemongrass contains a variety of substances that are known to have antioxidant and disease-preventing properties, including essential oils, compounds, minerals, and vitamins. Lemongrass (Cymbopogon Spp.) essential oil (LGEO) has been demonstrated to ameliorate diabetes and accelerate wound healing. A member of the Poaceae family, Lemongrass, a fragrant plant, is cultivated for the extraction of essential oils including myrcene and a mixture of geranial and neral isomers of citral monoterpenes. Active constituents in lemongrass essential oil are myrcene, followed by limonene and citral along with geraniol, citronellol, geranyl acetate, neral, and nerol, which are beneficial to human health. A large part of lemongrass' expansion is driven by the plant's huge industrial potential in the food, cosmetics, and medicinal sectors. A great deal of experimental and modeling study was conducted on the extraction of essential oils. Using Google Scholar and PubMed databases, a systematic review of the literature covering the period from 1996 to 2022 was conducted, in accordance with the PRISMA declaration. There were articles on chemistry, biosynthesis, extraction techniques and worldwide demand of lemongrass oil. We compared the effectiveness of several methods of extracting lemongrass essential oil, including solvent extraction, supercritical CO2 extraction, steam distillation, hydrodistillation (HD), and microwave aided hydrodistillation (MAHD). Moreover, essential oils found in lemongrass and its bioactivities have a significant impact on human health. This manuscript demonstrates the different extraction techniques of lemongrass essential oil and its physiological benefits on diabetic wound healing, tissue repair and regeneration, as well as its immense contribution in ameliorating arthritis and joint pain.Key teaching pointsThe international market demand prediction and the pharmacological benefits of the Lemongrass essential oil have been thoroughly reported here.This article points out that different extraction techniques yield different percentages of citral and other secondary metabolites from lemon grass, for example, microwave assisted hydrodistillation and supercritical carbon dioxide extraction process yields more citral.This article highlights the concept and application of lemongrass oil in aromatherapy, joint-pain, and arthritis.Moreover, this manuscript includes a discussion about the effect of lemongrass oil on diabetic wound healing and tissue regeneration - that paves the way for further research.
Collapse
Affiliation(s)
- Krishnendu Adhikary
- Department of Interdisciplinary Science, Centurion University of Technology and Management, Odisha, India
| | - Pradipta Banerjee
- Department of Surgery, University of Pittsburgh, Pennsylvania, USA
- Department of Biochemistry and Plant Physiology, Centurion University of Technology and Management, Odisha, India
| | - Saurav Barman
- Department of Agricultural Chemistry and Soil Science, Centurion University of Technology and Management, Odisha, India
| | - Bidyut Bandyopadhyay
- Department of Biochemistry and Biotechnology, Oriental Institute of Science and Technology, Burdwan, India
| | - Debasis Bagchi
- Department of Psychology, Gordon F. Derner School of Psychology, & Department of Biology, College of Arts and Sciences, Adelphi University, Garden City, New York, USA
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
| |
Collapse
|
41
|
Fumagalli V, Iannacone M. The interplay of drug therapeutics and immune responses to SARS-CoV-2. Cell Mol Immunol 2024; 21:197-200. [PMID: 37964122 PMCID: PMC10805708 DOI: 10.1038/s41423-023-01098-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/22/2023] [Indexed: 11/16/2023] Open
Abstract
The SARS-CoV-2 pandemic has necessitated rapid therapeutic and preventative responses. While vaccines form the frontline of defense, antiviral treatments such as nirmatrelvir have emerged as vital adjunctive measures, particularly for those unable or unwilling to be vaccinated. This review delves into the potential influence of nirmatrelvir on enduring immunity. In parallel, the potential of drug repurposing is explored, with bisphosphonates being examined for their possible effects against COVID-19 due to their immunomodulatory properties. The importance of rigorous clinical trials and careful interpretation of preliminary data is emphasized.
Collapse
Affiliation(s)
- Valeria Fumagalli
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
- Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| |
Collapse
|
42
|
Xu T, Gao S, Yang N, Zhao Q, Zhang Y, Li T, Liu Z, Han B. A personalized biomimetic dual-drug delivery system via controlled release of PTH 1-34 and simvastatin for in situ osteoporotic bone regeneration. Front Bioeng Biotechnol 2024; 12:1355019. [PMID: 38357710 PMCID: PMC10865375 DOI: 10.3389/fbioe.2024.1355019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024] Open
Abstract
Patients with osteoporosis often encounter clinical challenges of poor healing after bone transplantation due to their diminished bone formation capacity. The use of bone substitutes containing bioactive factors that increase the number and differentiation of osteoblasts is a strategy to improve poor bone healing. In this study, we developed an in situ dual-drug delivery system containing the bone growth factors PTH1-34 and simvastatin to increase the number and differentiation of osteoblasts for osteoporotic bone regeneration. Our system exhibited ideal physical properties similar to those of natural bone and allowed for customizations in shape through a 3D-printed scaffold and GelMA. The composite system regulated the sustained release of PTH1-34 and simvastatin, and exhibited good biocompatibility. Cell studies revealed that the composite system reduced osteoblast death, and promoted expression of osteoblast differentiation markers. Additionally, by radiographic analysis and histological observation, the dual-drug composite system demonstrated promising bone regeneration outcomes in an osteoporotic skull defect model. In summary, this composite delivery system, comprising dual-drug administration, holds considerable potential for bone repair and may serve as a safe and efficacious therapeutic approach for addressing bone defects in patients with osteoporosis.
Collapse
Affiliation(s)
- Tongtong Xu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, Jilin, China
| | - Shang Gao
- Department of Stomatology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Nan Yang
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Qi Zhao
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, Jilin, China
| | - Yutong Zhang
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
| | - Tieshu Li
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
| | - Zhihui Liu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Bing Han
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
| |
Collapse
|
43
|
Wei Z, Yu H, Zhao H, Wei M, Xing H, Pei J, Yang Y, Ren K. Broadening horizons: ferroptosis as a new target for traumatic brain injury. BURNS & TRAUMA 2024; 12:tkad051. [PMID: 38250705 PMCID: PMC10799763 DOI: 10.1093/burnst/tkad051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/24/2023] [Accepted: 10/15/2023] [Indexed: 01/23/2024]
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with ~50 million people experiencing TBI each year. Ferroptosis, a form of regulated cell death triggered by iron ion-catalyzed and reactive oxygen species-induced lipid peroxidation, has been identified as a potential contributor to traumatic central nervous system conditions, suggesting its involvement in the pathogenesis of TBI. Alterations in iron metabolism play a crucial role in secondary injury following TBI. This study aimed to explore the role of ferroptosis in TBI, focusing on iron metabolism disorders, lipid metabolism disorders and the regulatory axis of system Xc-/glutathione/glutathione peroxidase 4 in TBI. Additionally, we examined the involvement of ferroptosis in the chronic TBI stage. Based on these findings, we discuss potential therapeutic interventions targeting ferroptosis after TBI. In conclusion, this review provides novel insights into the pathology of TBI and proposes potential therapeutic targets.
Collapse
Affiliation(s)
- Ziqing Wei
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou, China
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, No. 1, Longhu Middle Ring Road, Jinshui District, Zhengzhou, China
| | - Haihan Yu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou, China
| | - Huijuan Zhao
- Henan International Joint Laboratory of Thrombosis and Hemostasis, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, No. 1, Longhu Middle Ring Road, Jinshui District, Luoyang, China
| | - Mingze Wei
- The Second Clinical Medical College, Harbin Medical University, No. 263, Kaiyuan Avenue, Luolong District, Harbin, China
| | - Han Xing
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, No. 246, Xuefu Road, Nangang District, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou 450052, China
| | - Jinyan Pei
- Quality Management Department, Henan No.3 Provincial People’s Hospital, No. 198, Funiu Road, Zhongyuan District, Henan province, Zhengzhou 450052, China
| | - Yang Yang
- Clinical Systems Biology Research Laboratories, Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, No. 198, Funiu Road, Zhongyuan District, Zhengzhou 450052, China
| | - Kaidi Ren
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, No. 246, Xuefu Road, Nangang District, Zhengzhou 450052, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou 450052, China
| |
Collapse
|
44
|
Nie M, Wu S, Chen Y, Wu Y, Chen R, Liu Y, Yue M, Jiang Y, Qiu D, Yang M, Wang Z, Gao J, Xiong H, Qi R, He J, Zhang J, Zhang L, Wang Y, Fang M, Que Y, Yao Y, Li S, Zhang J, Zhao Q, Yuan Q, Zhang T, Xia N. Micronanoparticled risedronate exhibits potent vaccine adjuvant effects. J Control Release 2024; 365:369-383. [PMID: 37972764 DOI: 10.1016/j.jconrel.2023.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/26/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Micro/Nano-scale particles are widely used as vaccine adjuvants to enhance immune response and improve antigen stability. While aluminum salt is one of the most common adjuvants approved for human use, its immunostimulatory capacity is suboptimal. In this study, we modified risedronate, an immunostimulant and anti-osteoporotic drug, to create zinc salt particle-based risedronate (Zn-RS), also termed particulate risedronate. Compared to soluble risedronate, micronanoparticled Zn-RS adjuvant demonstrated increased recruitment of innate cells, enhanced antigen uptake locally, and a similar antigen depot effect as aluminum salt. Furthermore, Zn-RS adjuvant directly and quickly stimulated immune cells, accelerated the formulation of germinal centers in lymph nodes, and facilitated the rapid production of antibodies. Importantly, Zn-RS adjuvant exhibited superior performance in both young and aged mice, effectively protecting against respiratory diseases such as SARS-CoV-2 challenge. Consequently, particulate risedronate showed great potential as an immune-enhancing vaccine adjuvant, particularly beneficial for vaccines targeting the susceptible elderly.
Collapse
Affiliation(s)
- Meifeng Nie
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Shuyu Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yiyi Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yangtao Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Ruitong Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yue Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Mingxi Yue
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yao Jiang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Dekui Qiu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Man Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Zikang Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Jiahua Gao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Hualong Xiong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Ruoyao Qi
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Jinhang He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Jinlei Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Liang Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yingbin Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Mujin Fang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Yuqiong Que
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Youliang Yao
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China
| | - Shaowei Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China.
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China.
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing 400016, China.
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China.
| | - Tianying Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China.
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, Xiamen University, Xiamen, Fujian 361102, China.
| |
Collapse
|
45
|
Almeida-Nunes DL, Silvestre R, Dinis-Oliveira RJ, Ricardo S. Enhancing Immunotherapy in Ovarian Cancer: The Emerging Role of Metformin and Statins. Int J Mol Sci 2023; 25:323. [PMID: 38203494 PMCID: PMC10779012 DOI: 10.3390/ijms25010323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.
Collapse
Affiliation(s)
- Diana Luísa Almeida-Nunes
- Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal;
- 1H-TOXRUN—One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
| | - Ricardo Silvestre
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4710-057 Braga, Portugal
| | - Ricardo Jorge Dinis-Oliveira
- 1H-TOXRUN—One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
- UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4169-007 Porto, Portugal
- Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4169-007 Porto, Portugal
- FOREN—Forensic Science Experts, 1400-136 Lisboa, Portugal
| | - Sara Ricardo
- Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal;
- 1H-TOXRUN—One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal;
- Faculty of Medicine, University of Porto, 4169-007 Porto, Portugal
| |
Collapse
|
46
|
Chan A, Torelli S, Cheng E, Batchelder R, Waliany S, Neal J, Witteles R, Nguyen P, Cheng P, Zhu H. Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2023; 25:715-735. [PMID: 38213548 PMCID: PMC10776491 DOI: 10.1007/s11936-023-01024-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/27/2023] [Indexed: 01/13/2024]
Abstract
Purpose of the Review Even as immune checkpoint inhibitors (ICIs) have transformed the lifespan of many patients, they may also trigger acceleration of long-term cardiovascular disease. Our review aims to examine the current landscape of research on ICI-mediated atherosclerosis and address key questions regarding its pathogenesis and impact on patient management. Recent Findings Preclinical mouse models suggest that T cell dysregulation and proatherogenic cytokine production are key contributors to plaque development after checkpoint inhibition. Clinical data also highlight the significant burden of atherosclerotic cardiovascular disease (ASCVD) in patients on immunotherapy, although the value of proactively preventing and treating ASCVD in this population remains an open area of inquiry. Current treatment options include dietary/lifestyle modification and traditional medications to manage hypertension, hyperlipidemia, and diabetes risk factors; no current targeted therapies exist. Summary Early identification of high-risk patients is crucial for effective preventive strategies and timely intervention. Future research should focus on refining screening tools, elucidating targetable mechanisms driving ICI atherosclerosis, and evaluating long-term cardiovascular outcomes in cancer survivors who received immunotherapy. Moreover, close collaboration between oncologists and cardiologists is essential to optimize patient outcomes.
Collapse
Affiliation(s)
- Antonia Chan
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Stefan Torelli
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Evaline Cheng
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Ryan Batchelder
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Sarah Waliany
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Joel Neal
- Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA USA
| | - Ronald Witteles
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
| | - Patricia Nguyen
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, 240 Pasteur Drive, Rm 3500, Biomedical Innovations Building, Stanford, CA 94304 USA
| | - Paul Cheng
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, 240 Pasteur Drive, Rm 3500, Biomedical Innovations Building, Stanford, CA 94304 USA
| | - Han Zhu
- Department of Medicine, Stanford University School of Medicine, Stanford, CA USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA USA
- Stanford Cardiovascular Institute and Department of Medicine, Stanford University, 240 Pasteur Drive, Rm 3500, Biomedical Innovations Building, Stanford, CA 94304 USA
| |
Collapse
|
47
|
Wang X, Geng S, Meng J, Kang N, Liu X, Xu Y, Lyu H, Xu Y, Xu X, Song X, Zhang B, Wang X, Nuerbulati N, Zhang Z, Zhai D, Mao X, Sun R, Wang X, Wang R, Guo J, Chen SW, Zhou X, Xia T, Qi H, Hu X, Shi Y. Foxp3-mediated blockage of ryanodine receptor 2 underlies contact-based suppression by regulatory T cells. J Clin Invest 2023; 133:e163470. [PMID: 38099494 PMCID: PMC10721146 DOI: 10.1172/jci163470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/10/2023] [Indexed: 12/18/2023] Open
Abstract
The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (Foxp3) expression has not been found. Here, we report that Foxp3 blocked the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shut down basal Ca2+ oscillation in Tregs, which reduced m-calpain activities that are needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency rendered the CD4+ T cell pool immune suppressive and caused it to behave in the same manner as Foxp3+ Tregs in viral infection, asthma, hypersensitivity, colitis, and tumor development. In the absence of Foxp3, Ryr2-deficient CD4+ T cells rescued the systemic autoimmunity associated with scurfy mice. Therefore, Foxp3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.
Collapse
Affiliation(s)
- Xiaobo Wang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Shuang Geng
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta, Canada
| | - Junchen Meng
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, and
| | - Ning Kang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Xinyi Liu
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Yanni Xu
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Huiyun Lyu
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Ying Xu
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Xun Xu
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Xinrong Song
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Bin Zhang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Xin Wang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Nuerdida Nuerbulati
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Ze Zhang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Di Zhai
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Xin Mao
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Ruya Sun
- Department of Basic Medical Sciences, School of Medicine, and
| | - Xiaoting Wang
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University and Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China
| | - Ruiwu Wang
- Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Jie Guo
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - S.R. Wayne Chen
- Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Xuyu Zhou
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Tie Xia
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
| | - Hai Qi
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
- Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China
| | - Xiaoyu Hu
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
- Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China
| | - Yan Shi
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua University, Beijing, China
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta, Canada
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
- Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China
| |
Collapse
|
48
|
Juarez D, Buono R, Matulis SM, Gupta VA, Duong M, Yudiono J, Paul M, Mallya S, Diep G, Hsin P, Lu A, Suh SM, Dong VM, Roberts AW, Leverson JD, Jalaluddin M, Liu Z, Bueno OF, Boise LH, Fruman DA. Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors. CANCER RESEARCH COMMUNICATIONS 2023; 3:2497-2509. [PMID: 37956312 PMCID: PMC10704957 DOI: 10.1158/2767-9764.crc-23-0350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023]
Abstract
The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.
Collapse
Affiliation(s)
- Dennis Juarez
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Roberta Buono
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Shannon M. Matulis
- Department of Hematology and Medical Oncology and the Winship Cancer Institute at Emory University, Atlanta, Georgia
| | - Vikas A. Gupta
- Department of Hematology and Medical Oncology and the Winship Cancer Institute at Emory University, Atlanta, Georgia
| | - Madeleine Duong
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Jacob Yudiono
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Madhuri Paul
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Sharmila Mallya
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Grace Diep
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Peter Hsin
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| | - Alexander Lu
- Department of Chemistry, University of California, Irvine, California
| | - Sang Mi Suh
- Department of Chemistry, University of California, Irvine, California
| | - Vy M. Dong
- Department of Chemistry, University of California, Irvine, California
| | | | | | | | | | | | - Lawrence H. Boise
- Department of Hematology and Medical Oncology and the Winship Cancer Institute at Emory University, Atlanta, Georgia
| | - David A. Fruman
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California
| |
Collapse
|
49
|
Guo C, Chi H. Immunometabolism of dendritic cells in health and disease. Adv Immunol 2023; 160:83-116. [PMID: 38042587 PMCID: PMC11086980 DOI: 10.1016/bs.ai.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2023]
Abstract
Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.
Collapse
Affiliation(s)
- Chuansheng Guo
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States.
| |
Collapse
|
50
|
Dong X, Xia S, Du S, Zhu MH, Lai X, Yao SQ, Chen HZ, Fang C. Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy. ACS CENTRAL SCIENCE 2023; 9:1864-1893. [PMID: 37901179 PMCID: PMC10604035 DOI: 10.1021/acscentsci.3c00702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Indexed: 10/31/2023]
Abstract
Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.
Collapse
Affiliation(s)
- Xiao Dong
- Department
of Pharmacy, School of Medicine, Shanghai
University, Shanghai 200444, China
| | - Shu Xia
- Department
of Pharmacy, School of Medicine, Shanghai
University, Shanghai 200444, China
| | - Shubo Du
- School
of Bioengineering, Dalian University of
Technology, Dalian 116024, China
| | - Mao-Hua Zhu
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
| | - Xing Lai
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
| | - Shao Q. Yao
- Department
of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Hong-Zhuan Chen
- Institute
of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Chao Fang
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
- Key
Laboratory of Basic Pharmacology of Ministry of Education & Joint
International Research Laboratory of Ethnomedicine of Ministry of
Education, Zunyi Medical University, Zunyi 563003, China
| |
Collapse
|