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Zhang J, Qu M, Mo Z, Sui H, Liu L, Fu D. Ionizable cationic lipid nanoparticles loaded with miRNA-125b/BLZ945 for pancreatic cancer treatment. Biotechnol Appl Biochem 2025; 72:846-857. [PMID: 39623756 DOI: 10.1002/bab.2701] [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: 03/10/2024] [Accepted: 11/12/2024] [Indexed: 04/29/2025]
Abstract
In prior research, both miRNA-125b and BLZ945 have shown potential in effectively inhibiting M2 macrophage polarization and producing antitumor effects. Nevertheless, their physicochemical characteristics present significant challenges for efficient in vivo delivery. Ionizable cationic lipid nanoparticles (LNPs), recognized for their superior biocompatibility and drug-loading capacity, serve as a novel carrier for nucleic acid-based therapeutics. In our study, we successfully encapsulated both agents within LNPs and conducted a thorough characterization. Subsequently, we investigated their potential to repolarize M2 macrophages in vitro and evaluated their in vivo distribution, biosafety, and antitumor efficacy. The findings revealed that the LNPs maintained excellent drug-loading efficiency, consistent particle size, and stable zeta potential. All formulations effectively inhibited M2 macrophage polarization in vitro. Upon administration in vivo, the LNPs not only demonstrated favorable biosafety profiles but also accumulated efficiently in tumor tissues, substantially reducing tumor burden, particularly notable in co-loaded LNPs. Our results affirm that LNPs are an effective carrier for miRNA-125b and BLZ945, highlighting this encapsulation approach as promising for the treatment of solid tumors and meriting further investigation. Practitioner points: (i) Ionizable cationic nanoparticles provide high and stable encapsulation rates to efficiently load nucleic acid polymers into the LNP, avoiding the rapid accumulation of circulating macrophages, which can lead to reduced penetration of the LNP into target tissues. Therefore, it can be used as a novel drug delivery method to benefit clinical patients. (ii) miRNA-125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients.
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Affiliation(s)
- Jiajie Zhang
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Department of Radiation Oncology, UNC School of Medicine, Chapel Hill, North Carolina, USA
| | - Ming Qu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Institute of Radiology Intervention, Changchun, China
| | - Zhanhao Mo
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Institute of Radiology Intervention, Changchun, China
| | - He Sui
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Institute of Radiology Intervention, Changchun, China
| | - Lin Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, China
- Jilin Institute of Radiology Intervention, Changchun, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Xu H, Fu X, Wang S, Ge Y, Zhang L, Li J, Zhang F, Yang Y, He Y, Sun Y, Gao A. Immunoglobulin-like transcript 5 polarizes M2-like tumor-associated macrophages for immunosuppression in non-small cell lung cancer. Int J Cancer 2025; 156:2225-2236. [PMID: 39910654 PMCID: PMC11970544 DOI: 10.1002/ijc.35360] [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: 02/20/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 02/07/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.
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Affiliation(s)
- Huijun Xu
- Jinan Central HospitalShandong UniversityJinanShandongChina
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Xuebing Fu
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Shuyun Wang
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Yihui Ge
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Lu Zhang
- Department of OncologyThe Fourth People's Hospital of ZiboZiboShandongChina
| | - Juan Li
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Fang Zhang
- Department of OncologyCentral Hospital affiliated to Shandong First Medical UniversityJinanShandongChina
| | - Yang Yang
- Department of Ultrasound, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Yifu He
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Yuping Sun
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Aiqin Gao
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
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Zhou H, Lao M, Liang Z, Zhao H, Wang Y, Huang Q, Ou C. Identification of M0 macrophage associated lipid metabolism genes for prognostic and immunotherapeutic response prediction in hepatocellular carcinoma. Discov Oncol 2025; 16:781. [PMID: 40377731 DOI: 10.1007/s12672-025-02620-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 05/08/2025] [Indexed: 05/18/2025] Open
Abstract
PURPOSE Liver cancer prognosis is associated with M0 macrophages and lipid metabolism reprogramming; however, the prognostic role of M0 macrophage-related lipid metabolism genes in hepatocellular carcinoma (HCC) remains unclear. METHODS We identified 153 lipid metabolism genes associated with M0 macrophage infiltration in HCC from The Cancer Genome Atlas (TCGA) and the Molecular Signatures Database (MSigDB). Prognostic genes were selected, and a model was constructed using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. The model was validated using the International Cancer Genome Consortium (ICGC) database. We assessed the expression levels of prognostic genes by quantitative real-time polymerase chain reaction (qRT‒PCR). RESULTS A prognostic model was developed based on five characteristic genes. Receiver operating characteristic curve analysis demonstrated that the model had good accuracy, with area under the curve values of 0.796, 0.732, and 0.728 for predicting survival at 1, 3, and 5 years, respectively. The high-risk group exhibited increased sensitivity to common chemotherapy drugs, including sorafenib, dasatinib, and 5-fluorouracil, compared with the low-risk group (P < 0.05). Additionally, the high-risk group had significantly more infiltrating M0 macrophages, resting dendritic cells, follicular helper T cells, and regulatory T cells than did the low-risk group (P < 0.05). The qRT‒PCR results confirmed the upregulation of these five characteristic genes in HCC tissues. CONCLUSIONS M0 macrophage-associated lipid metabolism genes may serve as biomarkers for the prognosis of patients with HCC and as targets for immunotherapy.
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Affiliation(s)
- Huanjie Zhou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Ming Lao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Zhengui Liang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Huiliu Zhao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Ying Wang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Qiongqing Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Chao Ou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
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Gou YK, Zhou J, Liu P, Wang MY. Research progress on monocyte/macrophage in the development of gastric cancer. Future Oncol 2025:1-11. [PMID: 40351251 DOI: 10.1080/14796694.2025.2504334] [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: 03/09/2024] [Accepted: 05/07/2025] [Indexed: 05/14/2025] Open
Abstract
Gastric cancer (GC) is diagnosed more than one million times each year and represents a major cause of cancer-related death worldwide. Although GC presents as a group of different types of disease, chronic inflammation has been strongly associated with tumorigenesis. Monocyte/macrophage play important roles in the development of inflammation and are vital components of the tumor microenvironment (TME). Monocyte/macrophage exert protumor and/or antitumor effects through the release of angiogenic and lymphangiogenic factors. Furthermore, tumor associated macrophages (TAMs) are emerging as key players in GC development. It is necessary to review and elucidate the roles of TAM subsets in GC and their molecular features. In this study, we focused on GC-related subsets of monocytes/macrophages and analyzed signaling related to TAMs in GC as well as the potential roles of these cells as therapeutic targets.
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Affiliation(s)
- Yuan-Kun Gou
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, PR China
| | - Jie Zhou
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, PR China
| | - Peng Liu
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, PR China
| | - Ming-Yi Wang
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, PR China
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, PR China
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Aggarwal A, Jana M, Singh A, Dam T, Maurya H, Pathak T, Orsulic S, Yang K, Chute D, Bishop JA, Faraji F, Thorstad WM, Koyfman S, Steward S, Shi Q, Sandulache V, Saba NF, Lewis JS, Corredor G, Madabhushi A. Artificial intelligence-based virtual staining platform for identifying tumor-associated macrophages from hematoxylin and eosin-stained images. Eur J Cancer 2025; 220:115390. [PMID: 40158294 PMCID: PMC12021545 DOI: 10.1016/j.ejca.2025.115390] [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: 03/04/2025] [Accepted: 03/19/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Virtual staining is an artificial intelligence-based approach that transforms pathology images between stain types, such as hematoxylin and eosin (H&E) to immunohistochemistry (IHC), providing a tissue-preserving and efficient alternative to traditional IHC staining. However, existing methods for translating H&E to virtual IHC often fail to generate images of sufficient quality for accurately delineating cell nuclei and IHC+ regions. To address these limitations, we introduce VISTA, an artificial intelligence-based virtual staining platform designed to translate H&E into virtual IHC. METHODS We applied VISTA to identify M2-subtype tumor-associated macrophages (M2-TAMs) in H&E images from 968 patients with HPV+ oropharyngeal squamous cell carcinoma across six institutional cohorts. M2-TAMs are a critical component of the tumor microenvironment, and their increased presence has been linked to poor survival. Co-registered H&E and CD163 + IHC tissue microarrays were used to train (D1, N = 102) and test (D2, N = 50) the VISTA platform. M2-TAM density, defined as the ratio of M2-TAMs to total nuclei, was derived from VISTA-generated CD163 + IHC images and evaluated for prognostic significance in additional training (D3, N = 360) and testing (D4, N = 456) cohorts using biopsy or resection H&E whole slide images. RESULTS High M2-TAM density was associated with worse overall survival in D4 (p = 0.0152, Hazard Ratio=1.63 [1.1-2.42]). VISTA outperformed existing methods, generating higher-quality virtual CD163 + IHC images in D2, with a Structural Similarity Index of 0.72, a Peak Signal-to-Noise Ratio of 21.5, and a Fréchet Inception Distance of 41.4. Additionally, VISTA demonstrated superior performance in segmenting M2-TAMs in D2 (Dice=0.74). CONCLUSION These findings establish VISTA as a computational platform for generating virtual IHC and facilitating the discovery of novel biomarkers from H&E images.
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Affiliation(s)
- Arpit Aggarwal
- Department of Biomedical Engineering, Georgia Tech, GA, USA; Department of Biomedical Engineering, Emory University, GA, USA
| | - Mayukhmala Jana
- Department of Biomedical Engineering, Georgia Tech, GA, USA; Department of Biomedical Engineering, Emory University, GA, USA
| | - Amritpal Singh
- Department of Biomedical Engineering, Emory University, GA, USA
| | - Tanmoy Dam
- Department of Biomedical Engineering, Emory University, GA, USA
| | - Himanshu Maurya
- Department of Biomedical Engineering, Emory University, GA, USA
| | - Tilak Pathak
- Department of Biomedical Engineering, Emory University, GA, USA
| | | | - Kailin Yang
- Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa Neuroscience Institute, University of Iowa, Iowa, IA, USA
| | - Deborah Chute
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
| | - Justin A Bishop
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Farhoud Faraji
- Department of Otolaryngology-Head and Neck Surgery, UC San Diego Health, La Jolla, CA, USA
| | - Wade M Thorstad
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MS, USA
| | - Shlomo Koyfman
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Scott Steward
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, GA, USA
| | - Qiuying Shi
- Department of Pathology and Laboratory Medicine, Oregon Health and Science University School of Medicine, OR, USA
| | - Vlad Sandulache
- Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, TX, USA; ENT Section, Operative CareLine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Emory University School of Medicine, GA, USA
| | - James S Lewis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, AZ, USA
| | - Germán Corredor
- Department of Biomedical Engineering, Georgia Tech, GA, USA; Department of Biomedical Engineering, Emory University, GA, USA; Atlanta VA Medical Center, GA, USA
| | - Anant Madabhushi
- Department of Biomedical Engineering, Georgia Tech, GA, USA; Department of Biomedical Engineering, Emory University, GA, USA; Atlanta VA Medical Center, GA, USA.
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de la Rosa I, Sisó P, Ríos C, Gracia J, Cuevas D, Maiques O, Eritja N, Soria X, Angel-Baldó J, Gatius S, Sanchez-Moral L, Sarrias MR, Matias-Guiu X, Martí RM, Macià A. High Copy Number Variations Correlate with a Pro-Tumoral Microenvironment and Worse Prognosis in Acral Lentiginous Melanoma. Int J Mol Sci 2025; 26:4097. [PMID: 40362334 PMCID: PMC12071846 DOI: 10.3390/ijms26094097] [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: 03/19/2025] [Revised: 04/16/2025] [Accepted: 04/19/2025] [Indexed: 05/15/2025] Open
Abstract
Acral lentiginous melanoma (ALM) is a rare melanoma subtype primarily located in acral regions. However, ALMs exhibit a distinctive genetic profile characterized by a high number of copy number variations (CNVs) and limited point mutations. Late diagnosis and restricted therapeutic efficacy contribute to its poor prognosis. The secretome within the tumor microenvironment (TME) influences immune modulation and plays a vital role in melanoma progression. We aim to analyze the role of ALM secretome and CNVs profile with prognosis in primary ALM patients. Here, we demonstrated that high CNV burden (CNVsHigh) was associated with worse clinicopathological characteristics and poor prognosis. Furthermore, our study also revealed that conditioned media (CM) of CNVsHigh genetic profile ALM cell line was associated with pro-tumoral, pro-angiogenic, and immunosuppressive secretome profiles. In addition, CM of CNVsHigh cell lines in vitro promotes macrophage polarization to immunosuppressive phenotype. Moreover, we observed an increased presence of immunosuppressive tumor-associated macrophages (TAMs) at the invasive front (IF) of CNVsHigh ALM biopsies. This research reveals the adverse prognostic impact of CNVsHigh in ALM patients, establishing a novel link with a pro-tumor secretome, offering potential biomarkers for prognosis and personalized treatment to enhanced disease monitoring in ALM patients.
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Affiliation(s)
- Inés de la Rosa
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Pol Sisó
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Christopher Ríos
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Judith Gracia
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
| | - Dolors Cuevas
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Oscar Maiques
- Cytoskeleton and Cancer Metastasis Group, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SM2 5NG, UK;
- Center for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK
| | - Núria Eritja
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Xavier Soria
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Joan Angel-Baldó
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Sonia Gatius
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Lidia Sanchez-Moral
- Innate Immunity Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; (L.S.-M.); (M.-R.S.)
| | - Maria-Rosa Sarrias
- Innate Immunity Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; (L.S.-M.); (M.-R.S.)
- Center for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), 28029 Madrid, Spain
| | - Xavier Matias-Guiu
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Rosa M. Martí
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
- Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Dermatology, Hospital Universitari Arnau de Vilanova de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (X.S.); (J.A.-B.)
| | - Anna Macià
- Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), University of Lleida, 25198 Lleida, Spain; (I.d.l.R.); (P.S.); (C.R.); (J.G.); (D.C.); (N.E.); (S.G.); (X.M.-G.)
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Fradin JJ, Charlson JA. Review of Adoptive Cellular Therapies for the Treatment of Sarcoma. Cancers (Basel) 2025; 17:1302. [PMID: 40282478 PMCID: PMC12026197 DOI: 10.3390/cancers17081302] [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: 02/21/2025] [Revised: 04/02/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease.
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Affiliation(s)
- James J. Fradin
- Division of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - John A. Charlson
- Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
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8
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Bhavsar V, Sahu A, Taware R. Stress-induced extracellular vesicles: insight into their altered proteomic composition and probable physiological role in cancer. Mol Cell Biochem 2025; 480:2025-2041. [PMID: 39302488 DOI: 10.1007/s11010-024-05121-x] [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: 04/17/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
EVs (extracellular vesicles) are phospholipid bilayer vesicles that can be released by both prokaryotic and eukaryotic cells in normal as well as altered physiological conditions. These vesicles also termed as signalosomes, possess a distinctive cargo comprising nucleic acids, proteins, lipids, and metabolites, enabling them to play a pivotal role in both local and long-distance intercellular communication. The composition, origin, and release of EVs can be influenced by different physiological conditions and a variety of stress factors, consequently affecting the contents carried within these vesicles. Therefore, identifying the modified contents of EVs can provide valuable insights into their functional role in stress-triggered communication. Particularly, this is important when EVs released from tumor microenvironment are investigated for their role in the development and dissemination of cancer. This review article emphasizes the importance of differential EV shedding and altered proteomic content in response to reduced oxygen concentration, altered levels of glucose and glutamine, pH variations, oxidative stress and Ca2+ ion concertation and it is subsequent effects on the behavior of recipient cells.
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Affiliation(s)
- Vaidehi Bhavsar
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ashish Sahu
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ravindra Taware
- Department of Natural Products, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India.
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9
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ZHAO SHUANG, WEN HONGYONG, WANG BAIQI, XIONG QINGLIN, LI LANXIN, CHENG AILAN. p53: A player in the tumor microenvironment. Oncol Res 2025; 33:795-810. [PMID: 40191727 PMCID: PMC11964878 DOI: 10.32604/or.2025.057317] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/09/2024] [Indexed: 04/09/2025] Open
Abstract
Approximately half of all cancers have p53 inactivating mutations, in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors, decreasing p53 activators, or inactivating p53 downstream targets. A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment (TME). TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients. p53 participates in host immunity and engages in the immune landscape of the TME, but the specific mechanisms remain to be investigated. This review briefly explores the interactions between different states of p53 and TME components and their mechanisms, as well as their effects on tumor progression. To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.
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Affiliation(s)
- SHUANG ZHAO
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - HONGYONG WEN
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - BAIQI WANG
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - QINGLIN XIONG
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - LANXIN LI
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - AILAN CHENG
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
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10
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Das G, Ptacek J, Campbell J, Li X, Havlinova B, Noonepalle SK, Villagra A, Barinka C, Novakova Z. Targeting prostate cancer by new bispecific monocyte engager directed to prostate-specific membrane antigen. PLoS One 2025; 20:e0307353. [PMID: 40096254 PMCID: PMC11913275 DOI: 10.1371/journal.pone.0307353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 01/28/2025] [Indexed: 03/19/2025] Open
Abstract
Prostate cancer (PCa) ranks as the second leading cause of cancer-related deaths among men in the United States. Prostate-specific membrane antigen (PSMA) represents a well-established biomarker of PCa, and its levels correlate positively with the disease progression, culminating at the stage of metastatic castration-resistant prostate cancer. Due to its tissue-specific expression and cell surface localization, PSMA shows superior potential for precise imaging and therapy of PCa. Antibody-based immunotherapy targeting PSMA offers the promise of selectively engaging the host immune system with minimal off-target effects. Here we report on the design, expression, purification, and characterization of a bispecific engager, termed 5D3-CP33, that efficiently recruits macrophages to the vicinity of PSMA-positive cancer cells mediating PCa death. The engager was engineered by fusing the anti-PSMA 5D3 antibody fragment to a cyclic peptide 33 (CP33), selectively binding the Fc gamma receptor I (FcγRI/CD64) on the surface of phagocytes. Functional parts of the 5D3-CP33 engager revealed a nanomolar affinity for PSMA and FcγRI/CD64 with dissociation constants of KD = 3 nM and KD = 140 nM, respectively. At a concentration as low as 0.3 nM, the engager was found to trigger the production of reactive oxygen species by U937 monocytic cells in the presence of PSMA-positive cells. Moreover, flow cytometry analysis demonstrated antibody-dependent cell-mediated phagocytosis of PSMA-positive cancer cells by U937 monocytes when exposed to 0.15 nM 5D3-CP33. Our findings illustrate that 5D3-CP33 effectively and specifically activates monocytes upon PSMA-positive target engagement, resulting in the elimination of tumor cells. The 5D3-CP33 engager can thus serve as a promising lead for developing new immunotherapy tools for the efficient treatment of PCa.
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Affiliation(s)
- Gargi Das
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Jakub Ptacek
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Jana Campbell
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Xintang Li
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America
| | - Barbora Havlinova
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Satish kumar Noonepalle
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America
| | - Alejandro Villagra
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., United States of America
| | - Cyril Barinka
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Zora Novakova
- Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic
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11
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Hacıosmanoğlu-Aldoğan E, Lama D, Yetke Hİ, Şenol H, Yöntem FD. Necroptotic Suppression of Lung Cancer Cell Proliferation and Migration: A Comprehensive In Vitro and In Silico Study to Determine New Molecular Targets for Pexidartinib. Cell Biochem Funct 2025; 43:e70068. [PMID: 40079395 DOI: 10.1002/cbf.70068] [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: 09/10/2024] [Revised: 02/19/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
In this study, the cytotoxic effects of pexidartinib (PLX), a tyrosine kinase inhibitor approved for tenosynovial giant cell tumor through inhibition of colony-stimulating factor 1 receptor (CSF1R), against A549 lung adenocarcinoma cells and Beas-2B healthy bronchial cells were investigated by in detailed in-vitro and in-silico studies. Through MTT assays, PLX demonstrated significant inhibition of A549 cell viability with IC50 values of 2.15 and 1.3 µM at 24 and 48 h, respectively, while having minimal effects on Beas-2B cells, with IC50 values of 36.2 and 9.3 µM. The high selectivity index indicates PLX's preferential action against cancerous cells. The mechanism of cell death induced by PLX was further explored using Annexin V/PI staining and flow cytometry, revealing that PLX primarily induces necrosis in A549 cells, with an increase in necrotic cell populations and reduced efficacy at higher concentrations. Western blot analysis showed an upregulation of necroptosis markers (RIP3 and pMLKL) in A549 cells, while apoptotic markers like Caspase-3 remained unchanged. In addition, wound healing assays demonstrated that PLX significantly inhibits A549 cell migration in a dose-dependent manner. Molecular docking studies identified key amino acids involved in PLX binding interactions with target proteins. RIPK1 showed the strongest binding affinity. MD simulations revealed that the PLX-VEGFR2 complex was the most stable. As conclusion, PLX, although approved for tenosynovial giant cell tumors, shows promising potential for lung adenocarcinoma treatment. It selectively inhibits cancer cell viability, induces necroptosis, and reduces cell migration. Its stronger binding to RIPK1 and VEGFR2 more than CSF1R.
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Affiliation(s)
- Ebru Hacıosmanoğlu-Aldoğan
- Department of Biophysics, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Fatih, Istanbul, Türkiye
| | - Dilhan Lama
- Faculty of Medicine, Bezmialem Vakif University, Fatih, Istanbul, Türkiye
| | - Hande İpek Yetke
- Department of Biophysics, Faculty of Medicine, Bezmialem Vakif University, Fatih, Istanbul, Türkiye
| | - Halil Şenol
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Bezmialem Vakif University, Fatih, Istanbul, Türkiye
| | - Fulya Dal Yöntem
- Department of Biophysics, School of Medicine, Koç University, Sarıyer, Istanbul, Türkiye
- Koç University Research Center for Translational Medicine (KUTTAM), Sarıyer, Istanbul, Türkiye
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12
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Naei VY, Tubelleza R, Monkman J, Sadeghirad H, Donovan ML, Blick T, Wicher A, Bodbin S, Viratham A, Stad R, Basu S, Cooper C, Barnett C, O'Byrne K, Ladwa R, Warkiani ME, Hughes BGM, Kulasinghe A. Spatial interaction mapping of PD-1/PD-L1 in head and neck cancer reveals the role of macrophage-tumour barriers associated with immunotherapy response. J Transl Med 2025; 23:177. [PMID: 39939997 PMCID: PMC11818323 DOI: 10.1186/s12967-025-06186-y] [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: 10/22/2024] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC). METHODS In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME. RESULTS Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes. CONCLUSION This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Rafael Tubelleza
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - James Monkman
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Habib Sadeghirad
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Meg L Donovan
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia
| | - Tony Blick
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | | | | | | | | | | | | | - Ken O'Byrne
- The Princess Alexandra Hospital, Brisbane, Australia
| | - Rahul Ladwa
- The Princess Alexandra Hospital, Brisbane, Australia
| | | | - Brett G M Hughes
- The Royal Brisbane and Women's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Arutha Kulasinghe
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
- Queensland Spatial Biology Centre, Wesley Research Institute, The Wesley Hospital, Brisbane, Australia.
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13
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Han T, Guo X, Xie J, Tong W, Zhang L. SUMO modified ETV1 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by facilitating CCL2 transcription in esophageal squamous cell carcinoma cells. Cancer Immunol Immunother 2025; 74:87. [PMID: 39891717 PMCID: PMC11787107 DOI: 10.1007/s00262-024-03914-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: 10/09/2024] [Accepted: 12/02/2024] [Indexed: 02/03/2025]
Abstract
OBJECTIVE Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME. METHODS Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay. RESULTS In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C-C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1. CONCLUSIONS Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.
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Affiliation(s)
- Tianci Han
- Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, 44 Xiaoheyan Road, Shenyang, China
- Department of Thoracic Surgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Shenyang, China
| | - Xiaoqi Guo
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Junwei Xie
- Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, 44 Xiaoheyan Road, Shenyang, China
- Department of Thoracic Surgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Shenyang, China
| | - Wei Tong
- Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, 44 Xiaoheyan Road, Shenyang, China
- Department of Thoracic Surgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Shenyang, China
| | - Liang Zhang
- Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, 44 Xiaoheyan Road, Shenyang, China.
- Department of Thoracic Surgery, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Shenyang, China.
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14
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Rawat S, Moglad E, Afzal M, Goyal A, Roopashree R, Bansal P, Mishra S, Prasad GVS, Pramanik A, Alzarea SI, Ali H, Imran M, Abida. Reprogramming tumor-associated macrophages: The role of MEK-STAT3 inhibition in lung cancer. Pathol Res Pract 2025; 265:155748. [PMID: 39616977 DOI: 10.1016/j.prp.2024.155748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 11/10/2024] [Accepted: 11/27/2024] [Indexed: 12/11/2024]
Abstract
Tumor-associated macrophages (TAMs) crucially contribute to lung cancer's advancement and escape from the immune system. TAMs, particularly the M2 phenotype, promote an immunosuppressive microenvironment, facilitating tumor growth and metastasis. The MEK-STAT3 signalling pathway is a critical mediator in this process, driving TAM reprogramming and contributing to lung cancer's resistance to treatment. Inhibiting the MEK and STAT3 pathways disrupts key cancer-promoting mechanisms, including immune evasion, angiogenesis, and metastasis. Preclinical studies have demonstrated the effectiveness of MEK inhibitors, such as trametinib and selumetinib, in synergistic therapies for NSCLC, particularly in modulating the tumor microenvironment. We analyse the present understanding of approaches that can transform TAMs via the inhibition of MEK-STAT3 with either solo or combined treatments in lung cancer therapy.
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Affiliation(s)
- Sushama Rawat
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India.
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, PO Box 6231, Jeddah 21442, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - R Roopashree
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Pooja Bansal
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Shivang Mishra
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf 72341, Saudi Arabia
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia; Center for Health Research, Northern Border University, Arar, Saudi Arabia
| | - Abida
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia; Center for Health Research, Northern Border University, Arar, Saudi Arabia
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15
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Cortellino S, D'Angelo M, Quintiliani M, Giordano A. Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer. J Cell Physiol 2025; 240:e31417. [PMID: 39245862 DOI: 10.1002/jcp.31417] [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: 04/28/2024] [Revised: 07/18/2024] [Accepted: 08/09/2024] [Indexed: 09/10/2024]
Abstract
Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.
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Affiliation(s)
- Salvatore Cortellino
- Laboratory of Molecular Oncology, Responsible Research Hospital, Campobasso, Italy
- Scuola Superiore Meridionale (SSM), School for Advanced Studies, Federico II University, Naples, Italy
- SHRO Italia Foundation ETS, Candiolo, Turin, Italy
| | - Margherita D'Angelo
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
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16
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Singer M, Zhang Z, Dayyani F, Zhang Z, Yaghmai V, Choi A, Valerin J, Imagawa D, Abi-Jaoudeh N. Modulation of Tumor-Associated Macrophages to Overcome Immune Suppression in the Hepatocellular Carcinoma Microenvironment. Cancers (Basel) 2024; 17:66. [PMID: 39796695 PMCID: PMC11718901 DOI: 10.3390/cancers17010066] [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: 12/16/2024] [Revised: 12/21/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs' depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs' depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice.
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Affiliation(s)
- Mahmoud Singer
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA; (Z.Z.); (Z.Z.); (V.Y.)
| | - Zhuoli Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA; (Z.Z.); (Z.Z.); (V.Y.)
| | - Farshid Dayyani
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92867, USA; (F.D.); (A.C.); (J.V.)
| | - Zigeng Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA; (Z.Z.); (Z.Z.); (V.Y.)
| | - Vahid Yaghmai
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA; (Z.Z.); (Z.Z.); (V.Y.)
| | - April Choi
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92867, USA; (F.D.); (A.C.); (J.V.)
| | - Jennifer Valerin
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92867, USA; (F.D.); (A.C.); (J.V.)
| | - David Imagawa
- Department of Surgery, University of California Irvine, Orange, CA 92697, USA;
| | - Nadine Abi-Jaoudeh
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA; (Z.Z.); (Z.Z.); (V.Y.)
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17
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Lauwers Y, De Groof TWM, Vincke C, Van Craenenbroeck J, Jumapili NA, Barthelmess RM, Courtoy G, Waelput W, De Pauw T, Raes G, Devoogdt N, Van Ginderachter JA. Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer. Proc Natl Acad Sci U S A 2024; 121:e2409668121. [PMID: 39693339 DOI: 10.1073/pnas.2409668121] [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: 05/26/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
Immunotherapies have emerged as an effective treatment option for immune-related diseases, such as cancer and inflammatory diseases. However, variations in patient responsiveness limit the broad applicability and success of these immunotherapies. Noninvasive whole-body imaging of the immune status of individual patients during immunotherapy could enable the prediction and monitoring of the patient's response, resulting in more personalized treatments. In this study, we developed a nanobody-based immunotracer targeting CD163, a receptor specifically expressed on macrophages. This anti-CD163 immunotracer bound to human and mouse CD163 with high affinity and specificity without competing for ligand binding. Furthermore, the tracer showed no unwanted immune cell activation and was nonimmunogenic. Upon radiolabeling of the anti-CD163 immunotracer, specific imaging of CD163+ macrophages using micro-single-photon emission computerized tomography/computed tomography or micro-positron emission tomography/CT was performed. The anti-CD163 immunotracer was able to stratify immunotherapy responders from nonresponders (NR) by visualizing differences in the intratumoral CD163+ TAM distribution in Lewis lung carcinoma-ovalbumin tumor-bearing mice receiving an anti-programmed cell death protein-1 (PD-1)/CSF1R combination treatment. Immunotherapy-responding mice showed a more homogeneous distribution of the PET signal in the middle of the tumor, while CD163+ TAMs were located at the tumor periphery in NR. As such, visualization of CD163+ TAM distribution in the tumor microenvironment could allow a prediction or follow-up of therapy response. Altogether, this study describes an immunotracer, specific for CD163+ macrophages, that allows same-day imaging and follow-up of these immune cells in the tumor microenvironment, providing a good basis for the prediction and follow-up of immunotherapy responses in cancer patients.
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Affiliation(s)
- Yoline Lauwers
- Molecular Imaging and Therapy Research Group, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Timo W M De Groof
- Molecular Imaging and Therapy Research Group, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Cécile Vincke
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Jolien Van Craenenbroeck
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Neema Ahishakiye Jumapili
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Romina Mora Barthelmess
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Guillaume Courtoy
- Department of Pathology, Universitair Ziekenhuis Brussel, Brussels B-1090, Belgium
- Laboratory of Experimental Pathology, Supporting Clinical Sciences, Vrije Universiteit Brussel, Brussels B-1090, Belgium
| | - Wim Waelput
- Department of Pathology, Universitair Ziekenhuis Brussel, Brussels B-1090, Belgium
- Laboratory of Experimental Pathology, Supporting Clinical Sciences, Vrije Universiteit Brussel, Brussels B-1090, Belgium
| | - Tessa De Pauw
- Molecular Imaging and Therapy Research Group, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Geert Raes
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Nick Devoogdt
- Molecular Imaging and Therapy Research Group, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Jo A Van Ginderachter
- Laboratory of Myeloid Cell Immunology, Vlaams Instituut voor Biotechnologie Center for Inflammation Research, Brussels 1050, Belgium
- Laboratory of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium
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18
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Jędrzejewski T, Sobocińska J, Maciejewski B, Spisz P, Walczak-Skierska J, Pomastowski P, Wrotek S. In vitro treatment of triple-negative breast cancer cells with an extract from the Coriolus versicolor mushroom changes macrophage properties related to tumourigenesis. Immunol Res 2024; 73:14. [PMID: 39680299 DOI: 10.1007/s12026-024-09574-6] [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: 05/06/2024] [Accepted: 10/21/2024] [Indexed: 12/17/2024]
Abstract
Macrophages, the most abundant cells that participate in tumour progression, are the subject of a number of anticancer therapy approaches. Our previous results revealed that an extract of the fungus Coriolus versicolor (CV) has anti-cancer and immunomodulatory properties. The aim of the present study was to investigate whether CV extract-treated triple-negative breast cancer (TNBC) cells can release factors that can reprogram macrophages from pro-tumourigenic to anti-cancer subtypes. RAW 264.7 macrophages were cultured in a conditioned medium (CM) from non-treated 4T1 breast cancer cells (CM-NT) or CV extract-stimulated cells (CM-CV). After treatment, the following macrophage properties were evaluated: cell viability; M1/M2 phenotype (enzyme activities: iNOS and arginase 1; and expression of CD molecules: CD80 and CD163); cytokine concentrations: IL-6, TNF-α, IL-10, TGF-β, MCP-1 and VEGF; migration level; and ROS production. The results revealed that, compared with normal cells, TNBC cells stimulated with CV extract create a microenvironment that promotes a decrease in macrophage viability and migration, intracellular ROS production, and pro-angiogenic cytokine production (VEGF and MCP-1). Moreover, CM-CV decreased the expression of M2 macrophage markers (arginase 1 and CD163; IL-10 and TGF-β) but upregulated the expression of M1 cell markers (iNOS and CD80; IL-6 and TNF-α). We concluded that CV extract modifies the tumour microenvironment and changes macrophage polarisation toward functioning as an anti-tumour agent. Therefore, it is promising to use in the treatment of TNBC-associated macrophages.
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Affiliation(s)
- Tomasz Jędrzejewski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland.
| | - Justyna Sobocińska
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Bartosz Maciejewski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Paulina Spisz
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Justyna Walczak-Skierska
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University in Toruń, Wileńska 4 Street, 87-100, Toruń, Poland
| | - Paweł Pomastowski
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University in Toruń, Wileńska 4 Street, 87-100, Toruń, Poland
- Department of Inorganic and Coordination Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7 Street, 87-100, Toruń, Poland
| | - Sylwia Wrotek
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
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19
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Gao B, Wang L, Wen T, Xie X, Rui X, Chen Q. Colon Cancer-Derived Exosomal LncRNA-XIST Promotes M2-like Macrophage Polarization by Regulating PDGFRA. Int J Mol Sci 2024; 25:11433. [PMID: 39518984 PMCID: PMC11545876 DOI: 10.3390/ijms252111433] [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: 08/01/2024] [Revised: 10/08/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Colon cancer ranks second in overall cancer-related deaths and poses a serious risk to human life and health. In recent years, exosomes are believed to play an important and significant role in cancer, especially tumor-derived exosomes (TDEs). Previous studies have highlighted the pivotal role of exosomes in tumor development, owing to their ability to mediate communication between tumor cells and macrophages, induce macrophage M2 polarization, and facilitate the progression of tumorigenesis. In this study, we revealed that colon cancer-derived exosomes promoted M2-like macrophage polarization. Moreover, exosome-induced M2-like macrophages, in turn, promoted the proliferation, migration, and invasion abilities of colon cancer cells. Specifically, CT26- and HCT116-derived exosomes led to the activation of AKT, ERK, and STAT3/6 signaling pathways in THP-1(Mφ) cells. Furthermore, our findings showed that colon cancer-derived exosomes secreted lncXIST to sponge miR-17-5p, which, in turn, promoted the expression of PDGFRA, a common gene found in all three signaling pathways, to facilitate M2-like macrophage polarization. Dual-luciferase reporter assays confirmed the binding relationship between lncXIST and miR-17-5p, as well as miR-17-5p and PDGFRA. Collectively, our results highlight the novel role of lncXIST in facilitating macrophage polarization by sponging miR-17-5p and regulating PDGFRA expression.
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Affiliation(s)
| | | | | | | | | | - Qiaoyi Chen
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710049, China; (B.G.); (L.W.); (T.W.); (X.X.); (X.R.)
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20
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Cao Y, Yi Y, Han C, Shi B. NF-κB signaling pathway in tumor microenvironment. Front Immunol 2024; 15:1476030. [PMID: 39493763 PMCID: PMC11530992 DOI: 10.3389/fimmu.2024.1476030] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 09/30/2024] [Indexed: 11/05/2024] Open
Abstract
The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.
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Affiliation(s)
- Yaning Cao
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
| | - Yanan Yi
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chongxu Han
- Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Bingwei Shi
- Department of Blood Transfusion, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, Jiangsu, China
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21
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Bai H, Feng L, Schmid F. Macrophage-based cancer immunotherapy: Challenges and opportunities. Exp Cell Res 2024; 442:114198. [PMID: 39103071 DOI: 10.1016/j.yexcr.2024.114198] [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: 05/25/2024] [Revised: 08/02/2024] [Accepted: 08/03/2024] [Indexed: 08/07/2024]
Abstract
Macrophages play crucial roles in the tumor microenvironment (TME), exerting diverse functions ranging from promoting tumor growth and metastasis to orchestrating anti-tumor immune responses. Their plasticity allows them to adopt distinct activation states, often called M1-like (pro-inflammatory) and M2-like (anti-inflammatory or pro-tumoral), significantly influencing tumor progression and response to therapy. Harnessing the potential of macrophages in cancer immunotherapy has emerged as a promising strategy, with increasing interest in targeting these cells directly or modulating their functions within the TME. This review explores the intricate interplay between macrophages, the TME, and immunotherapeutic approaches. We discuss the dynamic phenotypic and functional heterogeneity of tumor-associated macrophages (TAMs), their impact on disease progression, and the mechanisms underlying their response to immunotherapy. Furthermore, we highlight recent advancements in macrophage-based immunotherapeutic strategies, including macrophage-targeting agents, adoptive cell transfer, and engineering approaches. Understanding the complex crosstalk between macrophages and the TME is essential for developing effective immunotherapeutic interventions that exploit the immunomodulatory functions of macrophages to enhance anti-tumor immunity and improve clinical outcomes for cancer patients.
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Affiliation(s)
- Haotian Bai
- Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan, Jiangsu, 215316, China; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
| | - Li Feng
- Emergency Department, People's Hospital Affiliated to Shandong First Medical University, Jinan, 271100, Shandong Province, China.
| | - Felix Schmid
- School of Biomedical Sciences, Carleton University, Ottawa, Canada.
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22
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Nasir NJM, Chuah S, Shuen T, Prawira A, Ba R, Lim MC, Chua J, Nguyen PHD, Lim CJ, Wasser M, Hazirah SN, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Dan YY, Bonney GK, Chung A, Goh BKP, Chow PKH, Albani S, Zhai W, Ouyang JF, Toh HC, Chew V. GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma. Hepatol Commun 2024; 8:e0508. [PMID: 39167427 PMCID: PMC11340929 DOI: 10.1097/hc9.0000000000000508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/07/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC. METHODS HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence. RESULTS GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression. CONCLUSIONS Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression.
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Affiliation(s)
- N. Jannah M. Nasir
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
- Duke-NUS Medical School, Singapore
| | - Samuel Chuah
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Timothy Shuen
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Aldo Prawira
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Rebecca Ba
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Mei Chee Lim
- Duke-NUS Medical School, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Joelle Chua
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Phuong H. D. Nguyen
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Chun J. Lim
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Martin Wasser
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Sharifah N. Hazirah
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Tony K. H. Lim
- Duke-NUS Medical School, Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Wei Qiang Leow
- Duke-NUS Medical School, Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Tracy Jiezhen Loh
- Duke-NUS Medical School, Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Wei Keat Wan
- Duke-NUS Medical School, Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Yin Huei Pang
- Department of Pathology, National University Hospital, Singapore
| | - Gwyneth Soon
- Department of Pathology, National University Hospital, Singapore
| | - Peng Chung Cheow
- Duke-NUS Medical School, Singapore
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
| | - Juinn Huar Kam
- Duke-NUS Medical School, Singapore
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
| | - Shridhar Iyer
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University Surgical Cluster, National University Health System, Singapore
| | - Alfred Kow
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University Surgical Cluster, National University Health System, Singapore
| | - Yock Young Dan
- Department of Medicine, Division of Gastroenterology & Hepatology, National University Hospital, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Glenn K. Bonney
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University Surgical Cluster, National University Health System, Singapore
| | - Alexander Chung
- Duke-NUS Medical School, Singapore
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
| | - Brian K. P. Goh
- Duke-NUS Medical School, Singapore
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
| | - Pierce K. H. Chow
- Duke-NUS Medical School, Singapore
- Department of Hepatopancreatobiliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
- Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Centre, Singapore
| | - Salvatore Albani
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
| | - Weiwei Zhai
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore
- Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunan, China
| | | | - Han Chong Toh
- Duke-NUS Medical School, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore
- Duke-NUS Medical School, Singapore
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23
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Sezginer O, Unver N. Dissection of pro-tumoral macrophage subtypes and immunosuppressive cells participating in M2 polarization. Inflamm Res 2024; 73:1411-1423. [PMID: 38935134 PMCID: PMC11349836 DOI: 10.1007/s00011-024-01907-3] [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: 04/25/2024] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Alternatively activated macrophage (M2) polarization can result in one of four subtypes based on cytokines and signaling pathways associated with macrophage activation: M2a, M2b, M2c, and M2d macrophages. The majority of M2 subtypes are anti-inflammatory and pro-angiogenic, secreting growth factors (VEGF, PDGF) and matrix metalloproteinases (MMP2, MMP9) which boost tumor growth, metastasis, and invasion. M2-polarized macrophages are associated with immune suppressor cells harboring Myeloid derived suppressor cells, Regulatory T cells (Tregs), Regulatory B cells as well as alternatively activated (N2) neutrophils. Treg cells selectively support the metabolic stability, mitochondrial integrity, and survival rate of M2-like TAMs in an indirect environment. Also, the contribution of Breg cells influences macrophage polarization towards the M2 direction. TAM is activated when TAN levels in the tumor microenvironment are insufficient or vice versa, suggesting that macrophage and its polarization are fine-tuned. Understanding the functions of immune suppressive cells, mediators, and signaling pathways involved with M2 polarization will allow us to identify potential strategies for targeting the TAM repolarization phenotype for innovative immunotherapy approaches. In this review, we have highlighted the critical factors for M2 macrophage polarization, differential cytokine/chemokine profiles of M1 and M2 macrophage subtypes, and other immune cells' impact on the polarization within the immunosuppressive niche.
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Affiliation(s)
- Onurcan Sezginer
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Sihhiye, Ankara, 06100, Türkiye
| | - Nese Unver
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Sihhiye, Ankara, 06100, Türkiye.
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24
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Arshi A, Mahmoudi E, Raeisi F, Dehghan Tezerjani M, Bahramian E, Ahmed Y, Peng C. Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review. Front Immunol 2024; 15:1446937. [PMID: 39257589 PMCID: PMC11384988 DOI: 10.3389/fimmu.2024.1446937] [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: 06/10/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.
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Affiliation(s)
- Asghar Arshi
- Department of Biology, York University, Toronto, ON, Canada
| | - Esmaeil Mahmoudi
- Young Researchers and Elite Club, Islamic Azad University, Shahrekord, Iran
| | | | - Masoud Dehghan Tezerjani
- Department of bioinformatics, School of Advanced Medical Technologies, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Bahramian
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Yeasin Ahmed
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Chun Peng
- Department of Biology, York University, Toronto, ON, Canada
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25
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Zhang S, Deshpande A, Verma BK, Wang H, Mi H, Yuan L, Ho WJ, Jaffee EM, Zhu Q, Anders RA, Yarchoan M, Kagohara LT, Fertig EJ, Popel AS. Integration of Clinical Trial Spatial Multiomics Analysis and Virtual Clinical Trials Enables Immunotherapy Response Prediction and Biomarker Discovery. Cancer Res 2024; 84:2734-2748. [PMID: 38861365 PMCID: PMC12010747 DOI: 10.1158/0008-5472.can-24-0943] [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: 03/28/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
Due to the lack of treatment options, there remains a need to advance new therapeutics in hepatocellular carcinoma (HCC). The traditional approach moves from initial molecular discovery through animal models to human trials to advance novel systemic therapies that improve treatment outcomes for patients with cancer. Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential biomarkers for immunotherapy, we developed a new computational model to track tumor progression at the organ scale while capturing the spatial heterogeneity of the tumor in HCC. This computational model of spatial quantitative systems pharmacology was designed to simulate the effects of combination immunotherapy. The model was initiated using literature-derived parameter values and fitted to the specifics of HCC. Model validation was done through comparison with spatial multiomics data from a neoadjuvant HCC clinical trial combining anti-PD1 immunotherapy and a multitargeted tyrosine kinase inhibitor cabozantinib. Validation using spatial proteomics data from imaging mass cytometry demonstrated that closer proximity between CD8 T cells and macrophages correlated with nonresponse. We also compared the model output with Visium spatial transcriptomics profiling of samples from posttreatment tumor resections in the clinical trial and from another independent study of anti-PD1 monotherapy. Spatial transcriptomics data confirmed simulation results, suggesting the importance of spatial patterns of tumor vasculature and TGFβ in tumor and immune cell interactions. Our findings demonstrate that incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides a novel approach for patient outcome prediction and biomarker discovery. Significance: Incorporating mathematical modeling and computer simulations with high-throughput spatial multiomics data provides an effective approach for patient outcome prediction and biomarker discovery.
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Affiliation(s)
- Shuming Zhang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Atul Deshpande
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Babita K. Verma
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hanwen Wang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Haoyang Mi
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Long Yuan
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Won Jin Ho
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Elizabeth M. Jaffee
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Qingfeng Zhu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A. Anders
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Luciane T. Kagohara
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Elana J. Fertig
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Bloomberg-Kimmel Immunotherapy Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Applied Mathematics and Statistics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Jointly supervised research
| | - Aleksander S. Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Jointly supervised research
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26
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Wang B, Hu S, Teng Y, Chen J, Wang H, Xu Y, Wang K, Xu J, Cheng Y, Gao X. Current advance of nanotechnology in diagnosis and treatment for malignant tumors. Signal Transduct Target Ther 2024; 9:200. [PMID: 39128942 PMCID: PMC11323968 DOI: 10.1038/s41392-024-01889-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/04/2024] [Accepted: 06/02/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer remains a significant risk to human health. Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation. Nanomedicine shows great potential for cancer diagnosis and treatment. Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations. Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors. The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers. Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes, thus enhancing treatment outcomes while minimizing harm to healthy tissues. Simultaneously, nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors. This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors. According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites, we review the most recent developments in nanotechnology applications. Finally, we briefly discuss the prospects and challenges of nanotechnology in cancer.
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Affiliation(s)
- Bilan Wang
- Department of Pharmacy, Evidence-based Pharmacy Center, Children's Medicine Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Shiqi Hu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Yan Teng
- Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, P.R. China
| | - Junli Chen
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Haoyuan Wang
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yezhen Xu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Kaiyu Wang
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Jianguo Xu
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yongzhong Cheng
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| | - Xiang Gao
- Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
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Zhao Y, Ni Q, Zhang W, Yu S. Progress in reeducating tumor-associated macrophages in tumor microenvironment. Discov Oncol 2024; 15:312. [PMID: 39060648 PMCID: PMC11282027 DOI: 10.1007/s12672-024-01186-8] [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: 02/16/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
Malignant tumor, one of the most threatening diseases to human health, has been comprehensively treated with surgery, radiotherapy, chemotherapy and targeted therapy, but the prognosis has not always been ideal. In the past decade, immunotherapy has shown increased efficacy in tumor treatment; however, for immunotherapy to achieve its fullest potential, obstacles are to be conquered, among which tumor microenvironment (TME) has been widely investigated. In remodeling the tumor immune microenvironment to inhibit tumor progression, macrophages, as the most abundant innate immune population, play an irreplaceable role in the immune response. Therefore, how to remodel TME and alter the recruitment and polarization status of tumor-associated macrophages (TAM) has been of wide interest. In this context, nanoparticles, photodynamic therapy and other therapeutic approaches capable of affecting macrophage polarization have emerged. In this paper, we categorize and organize the existing means and methods for reprogramming TAM to provide ideas for clinical application of novel tumor-related therapies.
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Affiliation(s)
- Yiming Zhao
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, No.139, Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, China
| | - Qianyang Ni
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, No.139, Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, China
| | - Weijian Zhang
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, No.139, Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, China
| | - Suyang Yu
- Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, No.139, Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, China.
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Cheng Z, Fobian SF, Gurrieri E, Amin M, D'Agostino VG, Falahati M, Zalba S, Debets R, Garrido MJ, Saeed M, Seynhaeve ALB, Balcioglu HE, Ten Hagen TLM. Lipid-based nanosystems: the next generation of cancer immune therapy. J Hematol Oncol 2024; 17:53. [PMID: 39030582 PMCID: PMC11265205 DOI: 10.1186/s13045-024-01574-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
Immunotherapy has become an important part of the oncotherapy arsenal. Its applicability in various cancer types is impressive, as well as its use of endogenous mechanisms to achieve desired ends. However, off-target or on-target-off-tumor toxicity, limited activity, lack of control in combination treatments and, especially for solid tumors, low local accumulation, have collectively limited clinical use thereof. These limitations are partially alleviated by delivery systems. Lipid-based nanoparticles (NPs) have emerged as revolutionary carriers due to favorable physicochemical characteristics, with specific applications and strengths particularly useful in immunotherapeutic agent delivery. The aim of this review is to highlight the challenges faced by immunotherapy and how lipid-based NPs have been, and may be further utilized to address such challenges. We discuss recent fundamental and clinical applications of NPs in a range of areas and provide a detailed discussion of the main obstacles in immune checkpoint inhibition therapies, adoptive cellular therapies, and cytokine therapies. We highlight how lipid-based nanosystems could address these through either delivery, direct modulation of the immune system, or targeting of the immunosuppressive tumor microenvironment. We explore advanced and emerging liposomal and lipid nanoparticle (LNP) systems for nucleic acid delivery, intrinsic and extrinsic stimulus-responsive formulations, and biomimetic lipid-based nanosystems in immunotherapy. Finally, we discuss the key challenges relating to the clinical use of lipid-based NP immunotherapies, suggesting future research directions for the near term to realize the potential of these innovative lipid-based nanosystems, as they become the crucial steppingstone towards the necessary enhancement of the efficacy of immunotherapy.
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Affiliation(s)
- Ziyun Cheng
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Seth-Frerich Fobian
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Elena Gurrieri
- Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Mohamadreza Amin
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands
| | - Vito Giuseppe D'Agostino
- Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Mojtaba Falahati
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Sara Zalba
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarra Institute for Health Research, Pamplona, Spain
| | - Reno Debets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - María J Garrido
- Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarra Institute for Health Research, Pamplona, Spain
| | - Mesha Saeed
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ann L B Seynhaeve
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Hayri E Balcioglu
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Timo L M Ten Hagen
- Precision Medicine in Oncology (PrMiO), Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
- Nanomedicine Innovation Center Erasmus (NICE), Erasmus Medical Center, Rotterdam, The Netherlands.
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Wang H, Lou J, Liu H, Liu Y, Xie B, Zhang W, Xie J, Pan H, Han W. TRIM59 deficiency promotes M1 macrophage activation and inhibits colorectal cancer through the STAT1 signaling pathway. Sci Rep 2024; 14:16081. [PMID: 38992114 PMCID: PMC11239810 DOI: 10.1038/s41598-024-66388-0] [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: 05/07/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024] Open
Abstract
Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC.
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Affiliation(s)
- Haidong Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China
| | - Jun Lou
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China
| | - Hao Liu
- Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Yunlong Liu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China
| | - Binbin Xie
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China
| | - Wei Zhang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China
| | - Jiansheng Xie
- Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China.
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, Zhejiang, People's Republic of China.
- Department of Colorectal Medical Oncology, Zhejiang Cancer Hospital, No. 1, East Banshan Road, Gongshu District, Hangzhou, 310022, People's Republic of China.
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Lira GA, de Azevedo FM, Lins IGDS, Marques IDL, Lira GA, Eich C, de Araujo Junior RF. High M2-TAM Infiltration and STAT3/NF-κB Signaling Pathway as a Predictive Factor for Tumor Progression and Death in Cervical Cancer. Cancers (Basel) 2024; 16:2496. [PMID: 39061137 PMCID: PMC11275153 DOI: 10.3390/cancers16142496] [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: 06/05/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
INTRODUCTION The tumor microenvironment (TME) plays a crucial role in the progression, invasion, and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the CC TME, but studies on their correlation with CC progression are still controversial. This study aimed to investigate the relationship between TAM infiltration, the STAT3/NF-κB signaling pathway, and Overall Survival (OS) in CC patients. METHODS In a retrospective study, 691 CC patients who had received a definitive histopathologic diagnosis of CC scored by the FIGO staging system and not undergone preoperative treatment were selected from a database. The effect of TAM infiltration on tumor progression biomarkers using Tissue Microarray (TMA) and immunohistochemistry was evaluated. Furthermore, the impact of the expression of these biomarkers and clinical-pathological parameters on recurrence-free (RF) and OS using Kaplan-Meier and multivariable Cox regression methods was also analyzed. RESULTS High stromal CD163 + 204 + TAMs density and via STAT3 and NF-κB pathways was relevant to the expression of E-cadherin, Vimentin, MMP9, VEGFα, Bcl-2, Ki-67, CD25, MIF, FOXP3, and IL-17 (all p < 0.0001). In addition, elevated TNM staging IV had a strong association correlation with STAT3 and NF-κB pathways (p < 0.0001), CD25 (p < 0.001), VEGFα (p < 0.001), MIF (p < 0.0001), and Ki-67 (p < 0.0001). On the other hand, overall and recurrence survival was shown to be strongly influenced by the expression of SNAIL (HR = 1.52), E-cadherin (HR = 1.78), and Ki-67 (HR = 1.44). CONCLUSION M2-TAM and via STAT3/NF-κB pathways had a strong effect on CC tumor progression which reverberated in the severity of clinicopathological findings, becoming an important factor of poor prognosis.
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Affiliation(s)
- George Alexandre Lira
- Cancer and Inflammation Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte Natal, Natal 59072-970, RN, Brazil;
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte, Natal 59072-970, RN, Brazil;
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- League Against Cancer from Rio Grande do Norte, Advanced Oncology Center, Natal 59075-740, RN, Brazil; (I.G.d.S.L.); (G.A.L.)
| | | | | | - Isabelle de Lima Marques
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte, Natal 59072-970, RN, Brazil;
| | - Giovanna Afonso Lira
- League Against Cancer from Rio Grande do Norte, Advanced Oncology Center, Natal 59075-740, RN, Brazil; (I.G.d.S.L.); (G.A.L.)
| | - Christina Eich
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Raimundo Fernandes de Araujo Junior
- Cancer and Inflammation Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte Natal, Natal 59072-970, RN, Brazil;
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte, Natal 59072-970, RN, Brazil;
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
- Postgraduate Program in Functional and Structural Biology, Federal University of Rio Grande do Norte, Natal 59072-970, RN, Brazil
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Huang Y, Zhang Y, Duan X, Hou R, Wang Q, Shi J. Exploring the immune landscape and drug prediction of an M2 tumor-associated macrophage-related gene signature in EGFR-negative lung adenocarcinoma. Thorac Cancer 2024; 15:1626-1637. [PMID: 38886907 PMCID: PMC11260554 DOI: 10.1111/1759-7714.15375] [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: 12/27/2023] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Improving immunotherapy efficacy for EGFR-negative lung adenocarcinoma (LUAD) patients remains a critical challenge, and the therapeutic effect of immunotherapy is largely determined by the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the top-ranked immune infiltrating cells in the TME, and M2-TAMs exert potent roles in tumor promotion and chemotherapy resistance. An M2-TAM-based prognostic signature was constructed by integrative analysis of single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data to reveal the immune landscape and select drugs in EGFR-negative LUAD. METHODS M2-TAM-based biomarkers were obtained from the intersection of bulk RNA-seq data and scRNA-seq data. After consensus clustering of EGFR-negative LUAD into different clusters based on M2-TAM-based genes, we compared the prognosis, clinical features, estimate scores, immune infiltration, and checkpoint genes among the clusters. Next, we combined univariate Cox and LASSO regression analyses to establish an M2-TAM-based prognostic signature. RESULTS CCL20, HLA-DMA, HLA-DRB5, KLF4, and TMSB4X were verified as prognostic M2-like TAM-related genes by univariate Cox and LASSO regression analyses. IPS and TMB analyses revealed that the high-risk group responded better to common immunotherapy. CONCLUSION The study shows the potential of the M2-like TAM-related gene signature in EGFR-negative LUAD, explores the immune landscape based on M2-like TAM-related genes, and predict immunotherapy response of patients with EGFR-negative LUAD, providing a new insight for individualized treatment.
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Affiliation(s)
- Yajie Huang
- Department of Medical OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Yaozhong Zhang
- Department of Infectious DiseasesThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Xiaoyang Duan
- Department of Medical OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Ran Hou
- Department of Medical OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Qi Wang
- Department of EndoscopyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Jian Shi
- Department of Medical OncologyThe Fourth Hospital of Hebei Medical UniversityShijiazhuangChina
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Xu K, Dong M, Wu Z, Luo L, Xie F, Li F, Huang H, Wang F, Xiong X, Wen Z. Single-Cell RNA Sequencing Identifies Crucial Genes Influencing the Polarization of Tumor-Associated Macrophages in Liver Cancer. Int J Genomics 2024; 2024:7263358. [PMID: 38938448 PMCID: PMC11208785 DOI: 10.1155/2024/7263358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/15/2024] [Accepted: 05/06/2024] [Indexed: 06/29/2024] Open
Abstract
Background In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME). This investigation delves into the functional transformations of TAMs within the TME by leveraging single-cell transcriptomics to pinpoint critical genes influencing TAM subset polarization. Methods We procured single-cell and bulk transcriptomic data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), implementing quality assurance, dimensional reduction, clustering, and annotation on the single-cell sequencing data. To examine cellular interactions, CellChat was utilized, while single-cell regulatory network inference and clustering (SCENIC) was applied to deduce transcription factors (TFs) and their associated targets. Through gene enrichment, survival, and immune infiltration correlation analyses, we sought to pinpoint and validate influential genes. A TAM model under HCC conditions was then established to confirm the expression levels of these key genes. Results Our analysis encompassed 74,742 cells and 23,110 genes. Through postdimensional reduction and clustering, we identified seven distinct cell types and nine TAM subtypes. Analysis via CellChat highlighted a predominance of M2-phenotype-inclined TAM subsets within the tumor's core. SCENIC pinpointed the transcription factor PRDM1 and its target genes as pivotal in this region. Further analysis indicated these genes' involvement in macrophage polarization. Employing trajectory analysis, survival analysis, and immune infiltration correlation, we scrutinized and validated genes likely directing M2 polarization. Experimental validation confirmed PRDM1's heightened expression in TAMs conditioned by HCC. Conclusions Our findings suggest the PRDM1 gene is a key regulator of M2 macrophage polarization, contributing to the immunosuppressive TME in HCC.
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Affiliation(s)
- Kedong Xu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mingyi Dong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhengqiang Wu
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Linfei Luo
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fei Xie
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fan Li
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hongyan Huang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fenfen Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaofeng Xiong
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhili Wen
- Department of GastroenterologyThe Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Arora L, Patra D, Roy S, Nanda S, Singh N, Verma AK, Chakraborti A, Dasgupta S, Pal D. Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2 mediated monocyte infiltration. Mol Oncol 2024; 18:1278-1300. [PMID: 35658112 PMCID: PMC11077004 DOI: 10.1002/1878-0261.13260] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/24/2022] [Accepted: 06/02/2022] [Indexed: 11/09/2022] Open
Abstract
In most cancers, tumor hypoxia downregulates the expression of C-C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung-adenocarcinoma human samples for hypoxia-inducible factor 1-alpha (HIF-1A), microRNA-210-3p (mir-210-3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia-induced miR-210-3p in the regulation of CCL2 expression and macrophage polarization. HIF-1Α stabilization increases miR-210-3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR-210-3p directly binds to the 3'untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR-210-3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR-210-3p mimic-transfected HIF-1A silenced cancer cells. In contrast, inhibition of miR-210-3p in HIF-1A-overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti-hsa-miR-210-3p-locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR-210-3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.
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Affiliation(s)
- Leena Arora
- Department of Biomedical EngineeringIndian Institute of Technology RoparPunjabIndia
| | - Debarun Patra
- Department of Biomedical EngineeringIndian Institute of Technology RoparPunjabIndia
| | - Soumyajit Roy
- Department of Biomedical EngineeringIndian Institute of Technology RoparPunjabIndia
| | - Sidhanta Nanda
- Department of Biomedical EngineeringIndian Institute of Technology RoparPunjabIndia
| | - Navneet Singh
- Department of Pulmonary MedicinePostgraduate Institute of Medical Education & Research (PGIMER)ChandigarhIndia
| | - Anita K. Verma
- Department of Zoology, Kirori Mal CollegeUniversity of DelhiIndia
| | - Anuradha Chakraborti
- Department of Experimental Medicine & BiotechnologyPostgraduate Institute of Medical Education & Research (PGIMER)ChandigarhIndia
| | - Suman Dasgupta
- Department of Molecular Biology & BiotechnologyTezpur UniversityAssamIndia
| | - Durba Pal
- Department of Biomedical EngineeringIndian Institute of Technology RoparPunjabIndia
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Stefanidis E, Semilietof A, Pujol J, Seijo B, Scholten K, Zoete V, Michielin O, Sandaltzopoulos R, Coukos G, Irving M. Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells. J Clin Invest 2024; 134:e161660. [PMID: 38828721 PMCID: PMC11142748 DOI: 10.1172/jci161660] [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: 05/06/2022] [Accepted: 04/16/2024] [Indexed: 06/05/2024] Open
Abstract
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
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MESH Headings
- Animals
- Humans
- Mice
- Antigens, Differentiation/immunology
- Antigens, Neoplasm/immunology
- CD47 Antigen/immunology
- Cell Line, Tumor
- HLA-A2 Antigen/immunology
- HLA-A2 Antigen/genetics
- Immunotherapy, Adoptive
- Macrophages/immunology
- Macrophages/metabolism
- Phagocytosis
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Immunologic/immunology
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/genetics
- T-Lymphocytes/immunology
- Xenograft Model Antitumor Assays
- Male
- Female
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Affiliation(s)
- Evangelos Stefanidis
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Aikaterini Semilietof
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Julien Pujol
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - Bili Seijo
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - Kirsten Scholten
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - Vincent Zoete
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Olivier Michielin
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Precision Oncology, University Hospital of Geneva (HUG), Geneva, Switzerland
| | - Raphael Sandaltzopoulos
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - George Coukos
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - Melita Irving
- Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne (UNIL) and University Hospital of Lausanne (CHUV), Lausanne, Switzerland
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35
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Wang L, Wang W, Hu D, Liang Y, Liu Z, Zhong T, Wang X. Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives. Front Immunol 2024; 15:1346587. [PMID: 38690261 PMCID: PMC11058222 DOI: 10.3389/fimmu.2024.1346587] [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: 11/29/2023] [Accepted: 04/03/2024] [Indexed: 05/02/2024] Open
Abstract
Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.
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Affiliation(s)
- Lijuan Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weihua Wang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yan Liang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhanyu Liu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoling Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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36
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Kim SW, Kim CW, Moon YA, Kim HS. Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment. Anim Cells Syst (Seoul) 2024; 28:123-136. [PMID: 38577621 PMCID: PMC10993762 DOI: 10.1080/19768354.2024.2336249] [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: 01/25/2024] [Accepted: 03/17/2024] [Indexed: 04/06/2024] Open
Abstract
The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.
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Affiliation(s)
- Seung Woo Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Chan Woo Kim
- Cancer Immunotherapy Evaluation Team, Non-Clinical Evaluation Center, Osong Medical Innovation Foundation (KBIO Health), Cheongju, Republic of Korea
| | - Young-Ah Moon
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Hong Seok Kim
- Department of Molecular Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
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37
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Liu J, Yuan Q, Guo H, Guan H, Hong Z, Shang D. Deciphering drug resistance in gastric cancer: Potential mechanisms and future perspectives. Biomed Pharmacother 2024; 173:116310. [PMID: 38394851 DOI: 10.1016/j.biopha.2024.116310] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 02/07/2024] [Accepted: 02/17/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.
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Affiliation(s)
- Jiahua Liu
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qihang Yuan
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hui Guo
- First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hewen Guan
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Zhijun Hong
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Dong Shang
- First Affiliated Hospital of Dalian Medical University, Dalian, China.
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38
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Filippi A, Aurelian J, Mocanu MM. Analysis of the Gene Networks and Pathways Correlated with Tissue Differentiation in Prostate Cancer. Int J Mol Sci 2024; 25:3626. [PMID: 38612439 PMCID: PMC11011430 DOI: 10.3390/ijms25073626] [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: 01/30/2024] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Prostate cancer (PCa) is the most prevalent non-cutaneous cancer in men. Early PCa detection has been made possible by the adoption of screening methods based on the serum prostate-specific antigen and Gleason score (GS). The aim of this study was to correlate gene expression with the differentiation level of prostate adenocarcinomas, as indicated by GS. We used data from The Cancer Genome Atlas (TCGA) and included 497 prostate cancer patients, 52 of which also had normal tissue sample sequencing data. Gene ontology analysis revealed that higher GSs were associated with greater responses to DNA damage, telomere lengthening, and cell division. Positive correlation was found with transcription factor activator of the adenovirus gene E2 (E2F) and avian myelocytomatosis viral homolog (MYC) targets, G2M checkpoints, DNA repair, and mitotic spindles. Immune cell deconvolution revealed high M0 macrophage counts and an increase in M2 macrophages dependent on the GS. The molecular pathways most correlated with GSs were cell cycle, RNA transport, and calcium signaling (depleted). A combinatorial approach identified a set of eight genes able to differentiate by k-Nearest Neighbors (kNN) between normal tissues, low-Gleason tissues, and high-Gleason tissues with high accuracy. In conclusion, our study could be a step forward to better understanding the link between gene expression and PCa progression and aggressiveness.
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Affiliation(s)
- Alexandru Filippi
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Justin Aurelian
- Department of Specific Disciplines, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Urology, “Prof. Dr. Th. Burghele” Clinical Hospital, 050653 Bucharest, Romania
| | - Maria-Magdalena Mocanu
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
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39
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Choi JY, Seok HJ, Lee DH, Lee E, Kim TJ, Bae S, Shin I, Bae IH. Tumor-derived miR-6794-5p enhances cancer growth by promoting M2 macrophage polarization. Cell Commun Signal 2024; 22:190. [PMID: 38521953 PMCID: PMC10960442 DOI: 10.1186/s12964-024-01570-5] [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: 01/15/2024] [Accepted: 03/16/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Solid tumors promote tumor malignancy through interaction with the tumor microenvironment, resulting in difficulties in tumor treatment. Therefore, it is necessary to understand the communication between cells in the tumor and the surrounding microenvironment. Our previous study revealed the cancer malignancy mechanism of Bcl-w overexpressed in solid tumors, but no study was conducted on its relationship with immune cells in the tumor microenvironment. In this study, we sought to discover key factors in exosomes secreted from tumors overexpressing Bcl-w and analyze the interaction with the surrounding tumor microenvironment to identify the causes of tumor malignancy. METHODS To analyze factors affecting the tumor microenvironment, a miRNA array was performed using exosomes derived from cancer cells overexpressing Bcl-w. The discovered miRNA, miR-6794-5p, was overexpressed and the tumorigenicity mechanism was confirmed using qRT-PCR, Western blot, invasion, wound healing, and sphere formation ability analysis. In addition, luciferase activity and Ago2-RNA immunoprecipitation assays were used to study the mechanism between miR-6794-5p and its target gene SOCS1. To confirm the interaction between macrophages and tumor-derived miR-6794-5p, co-culture was performed using conditioned media. Additionally, immunohistochemical (IHC) staining and flow cytometry were performed to analyze macrophages in the tumor tissues of experimental animals. RESULTS MiR-6794-5p, which is highly expressed in exosomes secreted from Bcl-w-overexpressing cells, was selected, and it was shown that the overexpression of miR-6794-5p increased migratory ability, invasiveness, and stemness maintenance by suppressing the expression of the tumor suppressor SOCS1. Additionally, tumor-derived miR-6794-5p was delivered to THP-1-derived macrophages and induced M2 polarization by activating the JAK1/STAT3 pathway. Moreover, IL-10 secreted from M2 macrophages increased tumorigenicity by creating an immunosuppressive environment. The in vitro results were reconfirmed by confirming an increase in M2 macrophages and a decrease in M1 macrophages and CD8+ T cells when overexpressing miR-6794-5p in an animal model. CONCLUSIONS In this study, we identified changes in the tumor microenvironment caused by miR-6794-5p. Our study indicates that tumor-derived miR-6794-5p promotes tumor aggressiveness by inducing an immunosuppressive environment through interaction with macrophage.
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Affiliation(s)
- Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - Hyun Jeong Seok
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Dong Hyeon Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Eunju Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Tae-Jin Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Sangwoo Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.
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40
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Sturniolo I, Váróczy C, Regdon Z, Mázló A, Muzsai S, Bácsi A, Intili G, Hegedűs C, Boothby MR, Holechek J, Ferraris D, Schüler H, Virág L. PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype. Int J Mol Sci 2024; 25:3601. [PMID: 38612413 PMCID: PMC11011797 DOI: 10.3390/ijms25073601] [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: 02/15/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs.
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Affiliation(s)
- Isotta Sturniolo
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Csongor Váróczy
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- National Academy of Scientist Education, 4032 Debrecen, Hungary
| | - Zsolt Regdon
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
| | - Anett Mázló
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
| | - Szabolcs Muzsai
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
- Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, University of Debrecen, 4032 Debrecen, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.M.); (S.M.); (A.B.)
- HUN-REN-DE Allergology Research Group, 4032 Debrecen, Hungary
| | - Giorgia Intili
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy;
| | - Csaba Hegedűs
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
| | - Mark R. Boothby
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37235, USA;
| | | | - Dana Ferraris
- Department of Chemistry, McDaniel College, Westminster, MD 21157, USA;
| | - Herwig Schüler
- Center for Molecular Protein Science, Department of Chemistry, Lund University, 22100 Lund, Sweden;
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (C.V.); (Z.R.); (C.H.)
- HUN-REN-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
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41
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Vaccaro K, Allen J, Whitfield TW, Maoz A, Reeves S, Velarde J, Yang D, Meglan A, Ribeiro J, Blandin J, Phan N, Bell GW, Hata AN, Weiskopf K. Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction. J Clin Invest 2024; 134:e169315. [PMID: 38483480 PMCID: PMC11060739 DOI: 10.1172/jci169315] [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: 02/07/2023] [Accepted: 03/12/2024] [Indexed: 03/26/2024] Open
Abstract
Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed an unbiased, high-throughput screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we found that therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found that the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized antitumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations - including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of β2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
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Affiliation(s)
- Kyle Vaccaro
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Juliet Allen
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Troy W. Whitfield
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Asaf Maoz
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sarah Reeves
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - José Velarde
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Dian Yang
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Anna Meglan
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Juliano Ribeiro
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Jasmine Blandin
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Nicole Phan
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - George W. Bell
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Aaron N. Hata
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kipp Weiskopf
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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42
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Hurst R, Brewer DS, Gihawi A, Wain J, Cooper CS. Cancer invasion and anaerobic bacteria: new insights into mechanisms. J Med Microbiol 2024; 73:001817. [PMID: 38535967 PMCID: PMC10995961 DOI: 10.1099/jmm.0.001817] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/27/2024] [Indexed: 04/07/2024] Open
Abstract
There is growing evidence that altered microbiota abundance of a range of specific anaerobic bacteria are associated with cancer, including Peptoniphilus spp., Porphyromonas spp., Fusobacterium spp., Fenollaria spp., Prevotella spp., Sneathia spp., Veillonella spp. and Anaerococcus spp. linked to multiple cancer types. In this review we explore these pathogenic associations. The mechanisms by which bacteria are known or predicted to interact with human cells are reviewed and we present an overview of the interlinked mechanisms and hypotheses of how multiple intracellular anaerobic bacterial pathogens may act together to cause host cell and tissue microenvironment changes associated with carcinogenesis and cancer cell invasion. These include combined effects on changes in cell signalling, DNA damage, cellular metabolism and immune evasion. Strategies for early detection and eradication of anaerobic cancer-associated bacterial pathogens that may prevent cancer progression are proposed.
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Affiliation(s)
- Rachel Hurst
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
| | - Daniel S. Brewer
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
- Earlham Institute, Norwich Research Park Innovation Centre, Colney Lane, Norwich NR4 7UZ, UK
| | - Abraham Gihawi
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
| | - John Wain
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
- Quadram Institute Biosciences, Colney Lane, Norwich, Norfolk, NR4 7UQ, UK
| | - Colin S. Cooper
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK
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43
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Wang H, Wang X, Zhang X, Xu W. The promising role of tumor-associated macrophages in the treatment of cancer. Drug Resist Updat 2024; 73:101041. [PMID: 38198845 DOI: 10.1016/j.drup.2023.101041] [Citation(s) in RCA: 50] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 12/16/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024]
Abstract
Macrophages are important components of the immune system. Mature macrophages can be recruited to tumor microenvironment that affect tumor cell proliferation, invasion and metastasis, extracellular matrix remodeling, immune suppression, as well as chemotherapy resistance. Classically activated type I macrophages (M1) exhibited marked tumor killing and phagocytosis. Therefore, using macrophages for adoptive cell therapy has attracted attention and become one of the most effective strategies for cancer treatment. Through cytokines and/or chemokines, macrophage can inhibit myeloid cells recruitment, and activate anti-tumor and immune killing functions. Applying macrophages for anti-tumor delivery is one of the most promising approaches for cancer therapy. This review article introduces the role of macrophages in tumor development and drug resistance, and the possible clinical application of targeting macrophages for overcoming drug resistance and enhancing cancer therapeutics, as well as its challenges.
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Affiliation(s)
- Hongbin Wang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, PR China; Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin Medical University, PR China; Department of Surgical Oncology, Harbin Medical University Cancer Hospital, PR China.
| | - Xueying Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, PR China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, PR China
| | - Xin Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, PR China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, PR China
| | - Wanhai Xu
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, PR China; Heilongjiang Key Laboratory of Scientific Research in Urology, Harbin Medical University, PR China; Department of Urology, Harbin Medical University Cancer Hospital, PR China.
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Asadi M, Zarredar H, Zafari V, Soleimani Z, Saeedi H, Caner A, Shanehbandi D. Immune Features of Tumor Microenvironment: A Genetic Spotlight. Cell Biochem Biophys 2024; 82:107-118. [PMID: 37870699 DOI: 10.1007/s12013-023-01192-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 10/10/2023] [Indexed: 10/24/2023]
Abstract
A tumor represents a highly intricate tissue entity, characterized by an exceptionally complex microenvironment that starkly contrasts with the typical physiological surroundings of healthy tissues. Within this tumor microenvironment (TME), every component and factor assume paramount importance in the progression of malignancy and exerts a pivotal influence on a patient's clinical outcome. One of the remarkable aspects of the TME is its remarkable heterogeneity, not only across different types of cancers but even within the same histological category of tumors. In-depth research has illuminated the intricate interplay between specific immune cells and molecules and the dynamic characteristics of the TME. Recent investigations have yielded compelling evidence that several mutations harbored by tumor cells possess the capacity to instigate substantial alterations in the TME. These mutations, often acting as drivers of tumorigenesis, can orchestrate a cascade of events that remodel the TME, thereby influencing crucial aspects of cancer behavior, including its invasiveness, immune evasion, and response to therapies. It is within this nuanced context that the present study endeavors to provide a concise yet comprehensive summary of how specific mutations, within the genetic landscape of cancer cells, can instigate profound changes in TME features. By elucidating the intricate relationship between genetic mutations and the TME, this research aims to contribute to a deeper understanding of cancer biology. Ultimately, the knowledge gained from this study holds the potential to inform the development of more targeted and effective treatments, thereby offering new hope to patients grappling with the complexities of cancer.
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Affiliation(s)
- Milad Asadi
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Venus Zafari
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | - Zahra Soleimani
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Saeedi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayse Caner
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey.
- The University of Texas, MD Anderson Cancer Center, Houston, USA.
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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Choi TH, Yoo RJ, Park JY, Kim JY, Ann YC, Park J, Kim JS, Kim K, Shin YJ, Lee YJ, Lee KC, Park J, Chung H, Seok SH, Im HJ, Lee YS. Development of finely tuned liposome nanoplatform for macrophage depletion. J Nanobiotechnology 2024; 22:83. [PMID: 38424578 PMCID: PMC10903058 DOI: 10.1186/s12951-024-02325-7] [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: 04/13/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. RESULTS We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. CONCLUSION The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.
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Affiliation(s)
- Tae Hyeon Choi
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea
| | - Ran Ji Yoo
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, South Korea
- Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Ji Yong Park
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Ji Yoon Kim
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Young Chan Ann
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- School of Dentistry, Seoul National University, Seoul, South Korea
| | - Jeongbin Park
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea
| | - Jin Sil Kim
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyuwan Kim
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Yu Jin Shin
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Yong Jin Lee
- Division of Applied RI, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea
| | - Kyo Chul Lee
- Division of Applied RI, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea
| | - Jisu Park
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyewon Chung
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Hyeok Seok
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyung-Jun Im
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
- Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
| | - Yun-Sang Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea.
- Department of Nuclear Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, South Korea.
- Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
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Li J, Ma A, Zhang R, Chen Y, Bolyard C, Zhao B, Wang C, Pich T, Li W, Sun N, Ma Q, Wen H, Clinton SK, Carson WE, Li Z, Xin G. Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy. Cancer Immunol Immunother 2024; 73:52. [PMID: 38349405 PMCID: PMC10864225 DOI: 10.1007/s00262-023-03603-3] [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: 06/21/2023] [Accepted: 12/12/2023] [Indexed: 02/15/2024]
Abstract
INTRODUCTION As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.
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Affiliation(s)
- Jianying Li
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Anjun Ma
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Ruohan Zhang
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Yao Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chelsea Bolyard
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
| | - Bao Zhao
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Cankun Wang
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Thera Pich
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
| | - Wantong Li
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
| | - Nuo Sun
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Qin Ma
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Haitao Wen
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Steven K Clinton
- Department of Urology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - William E Carson
- Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Zihai Li
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA
| | - Gang Xin
- Department of Microbiology and Immunology, Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA.
- Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA.
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Asai Y, Yanagawa N, Osakabe M, Yamada N, Sugimoto R, Sato A, Ito K, Koike Y, Tanji T, Sakuraba M, Sato T, Sugai T. The clinicopathological impact of tumor-associated macrophages in patients with cutaneous malignant melanoma. J Surg Oncol 2024; 129:381-391. [PMID: 37916518 DOI: 10.1002/jso.27487] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/12/2023] [Accepted: 10/03/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are an immune component of the cutaneous malignant melanoma (CMM) microenvironment and affect tumor growth. TAMs can polarize into different phenotypes, that is, proinflammatory M1 and anti-inflammatory M2 macrophages. However, the role of the macrophage phenotype in CMM remains unclear. METHODS We examined 88 patients with CMM. Tissue microarrays were constructed, and the density of M1 and M2 macrophages was analyzed by immunohistochemistry. Immune cells coexpressing CD68 and phosphorylated signal transducer and activator of transcription 1 (pSTAT1) were considered M1 macrophages, whereas those coexpressing CD68 and c-macrophage activating factor (c-Maf) were defined as M2 macrophages. These TAMs were counted, and the relationships between the density of M1 and M2 macrophages and clinicopathological factors including prognosis were investigated. RESULTS The CD68/c-Maf score ranged from 0 to 34 (median: 5.5). The patients were divided based on the median score into the CD68/c-Maf high (≥5.5) and low (<5.5) expression groups. Univariate and multivariate analyses revealed that CD68/c-Maf expression was an independent predictive factor for progression-free survival and an independent prognostic factor for overall survival. CD68/pSTAT1 expression was found in only two patients. CONCLUSION We suggest that CD68/pSTAT1 coexpression is rarely observed in patients with CMM, and high CD68/c-Maf expression is a predictor of worse prognosis in these patients.
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Affiliation(s)
- Yoshinari Asai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
- Department of Plastic, Aesthetic and Reconstructive Surgery, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Noriyuki Yamada
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Ayaka Sato
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Kazuhiro Ito
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Yoshihiko Koike
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Takayuki Tanji
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Minoru Sakuraba
- Department of Plastic, Aesthetic and Reconstructive Surgery, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Takashi Sato
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba-cho, Shiwa-gun, Japan
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Wang J, Peng J, Chen Y, Nasser MI, Qin H. The role of stromal cells in epithelial-mesenchymal plasticity and its therapeutic potential. Discov Oncol 2024; 15:13. [PMID: 38244071 PMCID: PMC10799841 DOI: 10.1007/s12672-024-00867-8] [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: 06/11/2023] [Accepted: 01/15/2024] [Indexed: 01/22/2024] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a critical tumor invasion and metastasis process. EMT enables tumor cells to migrate, detach from their original location, enter the circulation, circulate within it, and eventually exit from blood arteries to colonize in foreign sites, leading to the development of overt metastases, ultimately resulting in death. EMT is intimately tied to stromal cells around the tumor and is controlled by a range of cytokines secreted by stromal cells. This review summarizes recent research on stromal cell-mediated EMT in tumor invasion and metastasis. We also discuss the effects of various stromal cells on EMT induction and focus on the molecular mechanisms by which several significant stromal cells convert from foes to friends of cancer cells to fuel EMT processes via their secretions in the tumor microenvironment (TME). As a result, a better knowledge of the role of stromal cells in cancer cells' EMT may pave the path to cancer eradication.
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Affiliation(s)
- Juanjing Wang
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Junmei Peng
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Yonglin Chen
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, China
| | - M I Nasser
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
| | - Hui Qin
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
- Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, China.
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Kostecki KL, Iida M, Crossman BE, Salgia R, Harari PM, Bruce JY, Wheeler DL. Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit. Cancers (Basel) 2024; 16:312. [PMID: 38254801 PMCID: PMC10814769 DOI: 10.3390/cancers16020312] [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: 11/28/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases-elimination, equilibrium, and escape-cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells.
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Affiliation(s)
- Kourtney L. Kostecki
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Bridget E. Crossman
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA;
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
| | - Justine Y. Bruce
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
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Hu Z, You L, Hu S, Yu L, Gao Y, Li L, Zhang S. Hepatocellular carcinoma cell-derived exosomal miR-21-5p promotes the polarization of tumor-related macrophages (TAMs) through SP1/XBP1 and affects the progression of hepatocellular carcinoma. Int Immunopharmacol 2024; 126:111149. [PMID: 38006750 DOI: 10.1016/j.intimp.2023.111149] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 10/18/2023] [Accepted: 10/28/2023] [Indexed: 11/27/2023]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have unique functions in the development of hepatocellular carcinoma (HCC). The tumor microenvironment is in a complex state in chronic disease. As a major participant in tumor-associated inflammation, TAMs have a unique effect on promoting tumor cell proliferation, angiogenesis and immunosuppression. The in-depth study of TAMs has important scientific and clinical value and provides new ideas for the treatment of cancer. METHODS Bioinformatics analysis, dual-luciferase reporter assays, RT-qPCR and clinical samples were used to analyze the potential mechanism of the miR-21-5p/SP1/XBP1 molecular axis in HCC. In this study, miR-21-5p was highly expressed in HCC exosomes compared with normal hepatocyte exosomes, and HCC exosomes containing miR-21-5p promoted the proliferation and migration of HCC cells and inhibited cell apoptosis. In addition, this treatment promoted the M2 polarization of macrophages, induced the expression of transcription factor-specific protein 1 (SP1), and inhibited the expression of X-box binding protein 1 (XBP1). However, these expression trends were reversed after inhibition of miR-21-5p expression in exosomes of hepatoma cells, and the effects of exosomal miR-21-5p were partially restored after overexpression of SP1. Animal experiments also verified that exosomal miR-21-5p in HCC cells affected the expression level of the SP1/XBP1 protein and promoted M2 polarization of TAMs. CONCLUSION Exosomal miR-21-5p in HCC cells can affect the development of HCC cells by regulating SP1/XBP1 and promoting the M2 polarization of TAMs, thereby affecting the adverse prognostic response of HCC patients.
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Affiliation(s)
- Zongqiang Hu
- Hepato-pancreato-biliary Surgery Department, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China; The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Liying You
- The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China; Department of Hepatology, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China
| | - Songqi Hu
- Hepato-pancreato-biliary Surgery Department, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China; The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Lu Yu
- The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China; Department of Pathology, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China
| | - Yang Gao
- Hepato-pancreato-biliary Surgery Department, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China; The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Li Li
- Hepato-pancreato-biliary Surgery Department, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China; The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
| | - Shengning Zhang
- Hepato-pancreato-biliary Surgery Department, First People's Hospital of Kunming City, Kunming, Yunnan 650032, China; The Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
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