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1
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Cui X, Song Y, Han J, Yuan Z. The multifaceted role of SMAD4 in immune cell function. Biochem Biophys Rep 2025; 41:101902. [PMID: 39802394 PMCID: PMC11721226 DOI: 10.1016/j.bbrep.2024.101902] [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: 08/30/2024] [Revised: 11/25/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.
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Affiliation(s)
- Xinmu Cui
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Yu Song
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
| | - Jianfeng Han
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
- Cellular Biomedicine Group Inc, Shanghai, 201203, China
| | - Zhaoxin Yuan
- Changchun Medical College, 6177, Jilin Street, Changchun, 130031, China
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2
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Gu C, Chen S, Huang L, Cao C, Yuan R, Kou Z, Chen W, Shi H, Gu X. Serum Cystatin S (CST4): A Novel Prognostic Marker for Gastric Cancer. Clin Med Insights Oncol 2025; 19:11795549241311404. [PMID: 39776666 PMCID: PMC11705353 DOI: 10.1177/11795549241311404] [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] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
Background Serum Cystatin S (CST4), a secretory protein that inhibits cellular matrix degradation, significantly influences the tumor microenvironment and tumor progression. However, the prognostic value of serum CST4 in gastric cancer (GC) remains unclear. This study aims to explore serum CST4's utility in GC prognostic assessment. Methods A cohort of 334 patients with GC who underwent radical gastrectomy was assessed. Preoperative serum CST4 levels were measured alongside traditional tumor markers, correlating with clinical data and patient outcomes. The cohort was divided into training and test sets at a ratio of 3:1 for Cox regression analyses, which identified CST4 as an independent risk factor for overall survival (OS) and disease-free survival (DFS). A prognostic model was developed, validated with calibration curves, and its predictive value was evaluated using receiver operating characteristic (ROC) curves. In addition, CST4 expression was correlated with immune cell infiltration using data from The Cancer Genome Atlas (TCGA). Patients were stratified by median CST4 levels, and Kaplan-Meier curves for OS and DFS were plotted. Results Cystatin S was confirmed as an independent risk factor for OS and DFS. Integrating CST4 with traditional markers and TNM pathological staging significantly enhanced the predictive value for prognosis. Cystatin S's impact on tumor progression is likely mediated through modulation of the immune microenvironment, including immune suppression and evasion. Conclusion Cystatin S is an effective biomarker for GC prognostic assessment, assisting in the evaluation of prognosis and the selection of treatment strategies for patients with GC.
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Affiliation(s)
- Chao Gu
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Shan Chen
- Department of Education, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Lining Huang
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Chenliang Cao
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Renshun Yuan
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Zhongyang Kou
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Weiwei Chen
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Haihua Shi
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xiaodong Gu
- Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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3
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Trugilo KP, Cebinelli GCM, Castilha EP, da Silva MR, Berti FCB, de Oliveira KB. The role of transforming growth factor β in cervical carcinogenesis. Cytokine Growth Factor Rev 2024; 80:12-23. [PMID: 39482191 DOI: 10.1016/j.cytogfr.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/03/2024]
Abstract
Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.
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Affiliation(s)
- Kleber Paiva Trugilo
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | | | - Eliza Pizarro Castilha
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | - Mariane Ricciardi da Silva
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | | | - Karen Brajão de Oliveira
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
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4
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Hamlin RE, Pienkos SM, Chan L, Stabile MA, Pinedo K, Rao M, Grant P, Bonilla H, Holubar M, Singh U, Jacobson KB, Jagannathan P, Maldonado Y, Holmes SP, Subramanian A, Blish CA. Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution. Sci Transl Med 2024; 16:eadr1032. [PMID: 39536117 DOI: 10.1126/scitranslmed.adr1032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor-β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2-like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.
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Affiliation(s)
- Rebecca E Hamlin
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Shaun M Pienkos
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Leslie Chan
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mikayla A Stabile
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kassandra Pinedo
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mallika Rao
- Stanford Center for Clinical Research, Stanford University, Stanford, CA 94305, USA
| | - Philip Grant
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hector Bonilla
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Marisa Holubar
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Upinder Singh
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Karen B Jacobson
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Kaiser Permanente Vaccine Study Center, Oakland, CA 94612, USA
| | - Prasanna Jagannathan
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yvonne Maldonado
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Susan P Holmes
- Department of Statistics, Stanford University, Stanford, CA 94305, USA
| | - Aruna Subramanian
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Catherine A Blish
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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5
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Liao JX, Huang QM, Pan ZC, Wu J, Zhang WJ. The anti-inflammatory and immunomodulatory effects of olfactory ensheathing cells transplantation in spinal cord injury and concomitant pathological pain. Eur J Pharmacol 2024; 982:176950. [PMID: 39214270 DOI: 10.1016/j.ejphar.2024.176950] [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: 04/26/2024] [Revised: 07/26/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice.
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Affiliation(s)
- Jun-Xiang Liao
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Qi-Ming Huang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Zhi-Cheng Pan
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Jie Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi province, China.
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Mo WT, Huang CF, Sun ZJ. Erythroid progenitor cell modulates cancer immunity: Insights and implications. Biochim Biophys Acta Rev Cancer 2024; 1879:189209. [PMID: 39549879 DOI: 10.1016/j.bbcan.2024.189209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 11/18/2024]
Abstract
The emergence of immunotherapies such as immune checkpoint blockade (ICB) has markedly enhanced cancer treatment outcomes for numerous patients. Nevertheless, the effectiveness of immunotherapy demonstrates substantial variation across different cancer types and individual patients. The immunosuppressive characteristics of the tumor microenvironment (TME) play a crucial role in contributing to this variation. Typically, people focus on cells with immunosuppressive functions in the TME, such as tumor-associated macrophages (TAMs), but research on TAMs alone cannot fully explain the complex structure and composition of the TME. Recent studies have reported that tumors can induce erythroid progenitor cells (EPCs) to exert immunosuppressive functions, not only acting within the TME but also secreting artemin in the spleen to promote tumor progression. In this review, we summarize the recent research on EPCs and tumors in recent years. We elucidate the mechanisms by which EPCs exert immunosuppressive functions in tumor-bearing conditions. In this review, we further propose potential therapeutic strategies targeting EPCs and emphasize the importance of in-depth exploration of the mechanisms by which EPCs regulate tumors and the immune system, as well as the significant clinical value of developing corresponding drugs.
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Affiliation(s)
- Wen-Tao Mo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Science, Wuhan University, Wuhan 430079, China
| | - Cong-Fa Huang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Science, Wuhan University, Wuhan 430079, China.
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Science, Wuhan University, Wuhan 430079, China.
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7
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Anfossi S, Darbaniyan F, Quinlan J, Calin S, Shimizu M, Chen M, Rausseo P, Winters M, Bogatenkova E, Do KA, Martinez I, Li Z, Antal L, Olariu TR, Wistuba I, Calin GA. MicroRNAs are enriched at COVID-19 genomic risk regions, and their blood levels correlate with the COVID-19 prognosis of cancer patients infected by SARS-CoV-2. Mol Cancer 2024; 23:235. [PMID: 39434078 PMCID: PMC11492698 DOI: 10.1186/s12943-024-02094-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/18/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes. PATIENTS AND METHODS Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR. RESULTS We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles. CONCLUSIONS MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients.
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Affiliation(s)
- Simone Anfossi
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
| | - Faezeh Darbaniyan
- Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Joseph Quinlan
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Steliana Calin
- Department of Hemopathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Masayoshi Shimizu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Meng Chen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Paola Rausseo
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Michael Winters
- Department of Microbiology, Immunology and Cell Biology, West Virginia University Cancer Institute, Morgantown, USA
| | - Elena Bogatenkova
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Kim-Anh Do
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Ivan Martinez
- Department of Microbiology, Immunology and Cell Biology, West Virginia University Cancer Institute, Morgantown, USA
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Loredana Antal
- Clinical Laboratory, Municipal Clinical Emergency Hospital, Timisoara, Romania
| | - Tudor Rares Olariu
- Clinical Laboratory, Municipal Clinical Emergency Hospital, Timisoara, Romania
- Department of Infectious Diseases, Center for Diagnosis and Study of Parasitic Diseases, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Ignacio Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.
- The Non-coding RNA Center, The University of Texas MD Anderson Cancer Center, Houston, USA.
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8
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Patsialos I, Kontandreopoulou CN, Vlachopoulou D, Stafylidis C, Syriopoulou S, Kalala F, Anastasopoulou A, Mantzourani M, Diamantopoulos P. A myelodysplastic neoplasm with del(5q) treated with luspatercept uncovers unexplored mechanisms of action for the drug. Br J Haematol 2024; 205:1641-1644. [PMID: 39155048 DOI: 10.1111/bjh.19708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 08/07/2024] [Indexed: 08/20/2024]
Affiliation(s)
- Iraklis Patsialos
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina-Nefeli Kontandreopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Vlachopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Stafylidis
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula Syriopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Fani Kalala
- Cancer Immunology Unit, Department of Immunology and Histocompatibility, School of Medicine, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Amalia Anastasopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Marina Mantzourani
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Diamantopoulos
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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9
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Hamlin RE, Pienkos SM, Chan L, Stabile MA, Pinedo K, Rao M, Grant P, Bonilla H, Holubar M, Singh U, Jacobson KB, Jagannathan P, Maldonado Y, Holmes SP, Subramanian A, Blish CA. Sex differences and immune correlates of Long COVID development, persistence, and resolution. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.18.599612. [PMID: 38948732 PMCID: PMC11212991 DOI: 10.1101/2024.06.18.599612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-β signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.
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Affiliation(s)
- Rebecca E. Hamlin
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Shaun M. Pienkos
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Leslie Chan
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Stanford Immunology Program, Stanford University School of Medicine; Stanford, CA, USA
| | - Mikayla A. Stabile
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Kassandra Pinedo
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Mallika Rao
- Stanford Center for Clinical Research, Stanford University; Stanford, CA, USA
| | - Philip Grant
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Hector Bonilla
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Marisa Holubar
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Upinder Singh
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine; Stanford, CA, USA
| | - Karen B. Jacobson
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Prasanna Jagannathan
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine; Stanford, CA, USA
| | - Yvonne Maldonado
- Department of Pediatrics, Stanford University School of Medicine; Stanford, CA, USA
| | - Susan P. Holmes
- Department of Statistics, Stanford University; Stanford, CA, USA
| | - Aruna Subramanian
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
| | - Catherine A. Blish
- Department of Medicine, Stanford University School of Medicine; Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University School of Medicine; Stanford, CA, USA
- Chan Zuckerberg Biohub; San Francisco, CA, USA
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10
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Bode K, Wei S, Gruber I, Li J, Kissler S, Yi P. Beta cells deficient for Renalase counteract autoimmunity by shaping natural killer cell activity. Front Immunol 2024; 15:1403752. [PMID: 38975343 PMCID: PMC11225407 DOI: 10.3389/fimmu.2024.1403752] [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: 03/19/2024] [Accepted: 05/14/2024] [Indexed: 07/09/2024] Open
Abstract
Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating the Renalase (Rnls) gene. Here, we demonstrate that Rnls loss of function in beta cells shapes autoimmunity by mediating a regulatory natural killer (NK) cell phenotype important for the induction of tolerogenic antigen-presenting cells. Rnls-deficient beta cells mediate cell-cell contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of regulatory NK immune checkpoints CD47 and Ceacam1 is markedly elevated on beta cells deficient for Rnls. Altered glucose metabolism in Rnls mutant beta cells is involved in the upregulation of CD47 surface expression. These findings are crucial to better understand how genetically engineered beta cells shape autoimmunity, giving valuable insights for future therapeutic advancements to treat and cure T1D.
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Affiliation(s)
- Kevin Bode
- Section for Immunobiology, Joslin Diabetes Center, Boston, MA, United States
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Siying Wei
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Isabella Gruber
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, United States
| | - Jian Li
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Stephan Kissler
- Section for Immunobiology, Joslin Diabetes Center, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, United States
| | - Peng Yi
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA, United States
- Department of Medicine, Harvard Medical School, Boston, MA, United States
- Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA, United States
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11
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Jafari-Raddani F, Davoodi-Moghaddam Z, Bashash D. Construction of immune-related gene pairs signature to predict the overall survival of multiple myeloma patients based on whole bone marrow gene expression profiling. Mol Genet Genomics 2024; 299:47. [PMID: 38649532 DOI: 10.1007/s00438-024-02140-7] [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: 03/23/2023] [Accepted: 04/06/2024] [Indexed: 04/25/2024]
Abstract
Multiple myeloma (MM) is a plasma cell dyscrasia that is characterized by the uncontrolled proliferation of malignant PCs in the bone marrow. Due to immunotherapy, attention has returned to the immune system in MM, and it appears necessary to identify biomarkers in this area. In this study, we created a prognostic model for MM using immune-related gene pairs (IRGPs), with the advantage that it is not affected by technical bias. After retrieving microarray data of MM patients, bioinformatics analyses like COX regression and least absolute shrinkage and selection operator (LASSO) were used to construct the signature. Then its prognostic value is assessed via time-dependent receiver operating characteristic (ROC) and the Kaplan-Meier (KM) analysis. We also used XCELL to examine the status of immune cell infiltration among MM patients. 6-IRGP signatures were developed and proved to predict MM prognosis with a P-value of 0.001 in the KM analysis. Moreover, the risk score was significantly associated with clinicopathological characteristics and was an independent prognostic factor. Of note, the combination of age and β2-microglobulin with risk score could improve the accuracy of determining patients' prognosis with the values of the area under the curve (AUC) of 0.73 in 5 years ROC curves. Our model was also associated with the distribution of immune cells. This novel signature, either alone or in combination with age and β2-microglobulin, showed a good prognostic predictive value and might be used to guide the management of MM patients in clinical practice.
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Affiliation(s)
- Farideh Jafari-Raddani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Davoodi-Moghaddam
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Crucitta S, Cucchiara F, Marconcini R, Bulleri A, Manacorda S, Capuano A, Cioni D, Nuzzo A, de Jonge E, Mathjissen RHJ, Neri E, van Schaik RHN, Fogli S, Danesi R, Del Re M. TGF-β mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma. Front Mol Biosci 2024; 11:1288677. [PMID: 38633217 PMCID: PMC11021649 DOI: 10.3389/fmolb.2024.1288677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/27/2024] [Indexed: 04/19/2024] Open
Abstract
Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-β (TGF-β) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-γ, and TGF-β were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-β expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8 months; p = 0.006) and overall survival (17.9 vs. 2.63 months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-β expression at baseline had smaller lesions (2.41 ± 3.27 mL vs. 42.79 ± 101.08 mL, p < 0.001) and higher dissimilarity (12.01 ± 28.23 vs. 5.65 ± 8.4; p = 0.018). Discussion: These results provide evidence that high TGF-β expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.
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Affiliation(s)
- Stefania Crucitta
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Federico Cucchiara
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Riccardo Marconcini
- Unit of Medical Oncology 2, Department of Medicine and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Alessandra Bulleri
- Unit of Radiodiagnostics 1, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Simona Manacorda
- Unit of Medical Oncology 2, Department of Medicine and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Annalisa Capuano
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Section of Pharmacology, Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Dania Cioni
- Unit of Radiodiagnostics 1, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Amedeo Nuzzo
- Unit of Medical Oncology 2, Department of Medicine and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Evert de Jonge
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Ron H. J. Mathjissen
- Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands
| | - Emanuele Neri
- Unit of Radiodiagnostics 1, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ron H. N. van Schaik
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Stefano Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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13
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Bode K, Wei S, Gruber I, Kissler S, Yi P. Beta Cells Deficient for Renalase Counteract Autoimmunity by Shaping Natural Killer Cell Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.29.582816. [PMID: 38496417 PMCID: PMC10942322 DOI: 10.1101/2024.02.29.582816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating of the Renalase (Rnls) gene. Here we demonstrate that Rnls loss-of-function in beta cells shape autoimmunity by mediating a regulatory Natural Killer (NK) cell phenotype important for the induction of tolerogenic antigen presenting cells. Rnls-deficient beta cells mediate cell-cell-contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of key regulatory NK immune checkpoints CD47 and Ceacam1 are markedly elevated on beta cells deficient for Rnls. Enhanced glucose metabolism in Rnls mutant beta cells is responsible for upregulation of CD47 surface expression. These findings are crucial to a better understand how genetically engineered beta cells shape autoimmunity giving valuable insights for future therapeutic advancements to treat and cure T1D.
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Affiliation(s)
- Kevin Bode
- Section for Immunobiology, Joslin Diabetes Center, Boston, MA 02215
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston MA 02115
| | - Siying Wei
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston MA 02115
| | - Isabella Gruber
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215
| | - Stephan Kissler
- Section for Immunobiology, Joslin Diabetes Center, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston MA 02115
- Diabetes Program, Harvard Stem Cell Institute, Cambridge MA 02138
| | - Peng Yi
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215
- Department of Medicine, Harvard Medical School, Boston MA 02115
- Diabetes Program, Harvard Stem Cell Institute, Cambridge MA 02138
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14
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Dorjkhorloo G, Erkhem-Ochir B, Shiraishi T, Sohda M, Okami H, Yamaguchi A, Shioi I, Komine C, Nakazawa N, Ozawa N, Shibasaki Y, Okada T, Osone K, Sano A, Sakai M, Ogawa H, Yokobori T, Shirabe K, Saeki H. Prognostic value of a modified‑immune scoring system in patients with pathological T4 colorectal cancer. Oncol Lett 2024; 27:104. [PMID: 38298428 PMCID: PMC10829066 DOI: 10.3892/ol.2024.14237] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/13/2023] [Indexed: 02/02/2024] Open
Abstract
Tumor-infiltrating immune cells, such as lymphocytes and macrophages, have been associated with tumor aggressiveness, prognosis and treatment response in colorectal cancer (CRC). An immune scoring system, Immunoscore (IS), based on tumor-infiltrating T cells in stage I-III CRC, was used to predict prognosis. An alternative immune scoring signature of immune activation (SIA) reflects the balance between anti- and pro-tumoral immune components. The present study aimed to evaluate the prognostic value of modified IS (mIS) and modified SIA (mSIA) in locally advanced pathological T4 (pT4) CRC, including stage IV CRC. Immunohistochemical staining for immune cell markers, such as CD3 (pan-T cell marker), CD8 (anti-tumoral cytotoxic T cell marker) and CD163 (tumor-supportive macrophage marker), in specimens from patients with radically resected pT4 CRC at stages II-IV was performed. mIS levels in the T4 CRC cohort were not associated with prognosis. However, low mSIA levels were associated with low survival. Furthermore, low mSIA was an independent predictor of recurrence in patients with radically resected pT4 CRC. In patients with CRC who did not receive postoperative adjuvant chemotherapy, low mSIA was a major poor prognostic factor; however, this was not observed in patients receiving adjuvant chemotherapy. Evaluation of the tumor-infiltrating immune cell population could serve as a valuable marker of recurrence and poor prognosis in patients with locally advanced CRC. mSIA assessment after radical CRC resection may be promising for identifying high-risk patients with pT4 CRC who require aggressive adjuvant chemotherapy.
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Affiliation(s)
- Gendensuren Dorjkhorloo
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Bilguun Erkhem-Ochir
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma 371-8511, Japan
| | - Takuya Shiraishi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Arisa Yamaguchi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Ikuma Shioi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Chika Komine
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Nobuhiro Nakazawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Naoya Ozawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Yuta Shibasaki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Takuhisa Okada
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Katsuya Osone
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Gunma 371-8511, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan
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15
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Kim W, Ye Z, Simonenko V, Shahi A, Malikzay A, Long S, Xu JJ, Lu A, Horng JH, Wu CR, Chen PJ, Lu P, Evans DM. Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors. NAR Cancer 2024; 6:zcad059. [PMID: 38204925 PMCID: PMC10776204 DOI: 10.1093/narcan/zcad059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/11/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Upregulation of TGFβ and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFβ and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFβ and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFβ and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.
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Affiliation(s)
- Wookhyun Kim
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Zhou Ye
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Vera Simonenko
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Aashirwad Shahi
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Asra Malikzay
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Steven Z Long
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - John J Xu
- Suzhou Sirnaomics Pharmaceuticals, Ltd., Biobay, Suzhou, China
| | - Alan Lu
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - Jau-Hau Horng
- National Taiwan University College of Medicine, No. 1, Section 1, Ren’ai Rd, Zhongzheng District, Taipei City 100, Taiwan
| | - Chang-Ru Wu
- National Taiwan University College of Medicine, No. 1, Section 1, Ren’ai Rd, Zhongzheng District, Taipei City 100, Taiwan
| | - Pei-Jer Chen
- National Taiwan University College of Medicine, No. 1, Section 1, Ren’ai Rd, Zhongzheng District, Taipei City 100, Taiwan
| | - Patrick Y Lu
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
| | - David M Evans
- Sirnaomics Inc., 20511 Seneca Meadows Parkway, Suite 200, Germantown, MD 20876, USA
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16
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Li C, Guo H, Zhai P, Yan M, Liu C, Wang X, Shi C, Li J, Tong T, Zhang Z, Ma H, Zhang J. Spatial and Single-Cell Transcriptomics Reveal a Cancer-Associated Fibroblast Subset in HNSCC That Restricts Infiltration and Antitumor Activity of CD8+ T Cells. Cancer Res 2024; 84:258-275. [PMID: 37930937 PMCID: PMC10790129 DOI: 10.1158/0008-5472.can-23-1448] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 09/14/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023]
Abstract
Although immunotherapy can prolong survival in some patients with head and neck squamous cell carcinoma (HNSCC), the response rate remains low. Clarification of the critical mechanisms regulating CD8+ T-cell infiltration and dysfunction in the tumor microenvironment could help maximize the benefit of immunotherapy for treating HNSCC. Here, we performed spatial transcriptomic analysis of HNSCC specimens with differing immune infiltration and single-cell RNA sequencing of five pairs of tumor and adjacent tissues, revealing specific cancer-associated fibroblast (CAF) subsets related to CD8+ T-cell infiltration restriction and dysfunction. These CAFs exhibited high expression of CXCLs (CXCL9, CXCL10, and CXCL12) and MHC-I and enrichment of galectin-9 (Gal9). The proportion of MHC-IhiGal9+ CAFs was inversely correlated with abundance of a TCF1+GZMK+ subset of CD8+ T cells. Gal9 on CAFs induced CD8+ T-cell dysfunction and decreased the proportion of tumor-infiltrating TCF1+CD8+ T cells. Collectively, the identification of MHC-IhiGal9+ CAFs advances the understanding of the precise role of CAFs in cancer immune evasion and paves the way for more effective immunotherapy for HNSCC. SIGNIFICANCE Spatial analysis identifies IFN-induced MHC-IhiGal9+ CAFs that form a trap for CD8+ T cells, providing insights into the complex networks in the tumor microenvironment that regulate T-cell infiltration and function.
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Affiliation(s)
- Chuwen Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Haiyan Guo
- Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Peisong Zhai
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Ming Yan
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Chun Liu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Xiaoning Wang
- Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Chaoji Shi
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Jiang Li
- Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Tong Tong
- Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai, People's Republic of China
| | - Zhiyuan Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China
| | - Hailong Ma
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
| | - Jianjun Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- National Center for Stomatology, Shanghai, People's Republic of China
- National Clinical Research Center for Oral Diseases, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Stomatology, Shanghai, People's Republic of China
- Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China
- Shanghai Center of Head and Neck Oncology Clinical and Translational Science, Shanghai, People's Republic of China
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Kaur H, Ali SA, Short SP, Williams CS, Goettel JA, Washington MK, Peek RM, Acra SA, Yan F. Identification of a functional peptide of a probiotic bacterium-derived protein for the sustained effect on preventing colitis. Gut Microbes 2023; 15:2264456. [PMID: 37815528 PMCID: PMC10566403 DOI: 10.1080/19490976.2023.2264456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/25/2023] [Indexed: 10/11/2023] Open
Abstract
Several probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1-28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a β-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28-120 residues) and p40N180 (28-180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.
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Affiliation(s)
- Harpreet Kaur
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Syed Azmal Ali
- Division of Proteomics of Stem Cell and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Sarah P. Short
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Jeremy A. Goettel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M. Kay Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sari A. Acra
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Fang Yan
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
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18
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Sun Q, Cai D, Liu D, Zhao X, Li R, Xu W, Xie B, Gou M, Wei K, Li Y, Huang J, Chi X, Wei P, Hao J, Guo X, Pan B, Fu Y, Ni L, Dong C. BCL6 promotes a stem-like CD8 + T cell program in cancer via antagonizing BLIMP1. Sci Immunol 2023; 8:eadh1306. [PMID: 37862431 DOI: 10.1126/sciimmunol.adh1306] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 08/30/2023] [Indexed: 10/22/2023]
Abstract
Overcoming CD8+ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8+ T cell (Tprog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8+ T cell (Tterm cell) subpopulation with potent cytotoxic functions. Tprog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control Tprog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific Tterm cell generation from Tprog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of Tprog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX+TCF1+ Tprog cells in both LNs and tumors. BCL6 expression in CD8+ T cells was up-regulated by TGF-β-SMAD2 signaling but down-regulated by the IL-2-STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of Tterm cell-associated genes and induced those of Tprog cell-related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the Tprog cell program and greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-β-BCL6 and IL-2-BLIMP1 antagonistic pathways in regulation of antitumor CD8+ T cells, which may benefit the development of long-lasting and effective cancer immunotherapy.
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Affiliation(s)
- Qinli Sun
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Dongli Cai
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
- Department of Gynaecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China
| | - Dingfeng Liu
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
- Department of Gynaecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China
| | - Xiaohong Zhao
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ruifeng Li
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Wei Xu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Bowen Xie
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Mengting Gou
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
| | - Kun Wei
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yuling Li
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- College of Life Science and Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Tsinghua University, Beijing 100084, China
| | - Jinling Huang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xinxin Chi
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Peng Wei
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jing Hao
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
| | - Xinyi Guo
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
| | - Birui Pan
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Yujie Fu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
| | - Ling Ni
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
- Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China
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19
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Chan HY, Tran HM, Breen J, Schjenken JE, Robertson SA. The endometrial transcriptome transition preceding receptivity to embryo implantation in mice. BMC Genomics 2023; 24:590. [PMID: 37794337 PMCID: PMC10552439 DOI: 10.1186/s12864-023-09698-3] [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: 02/05/2023] [Accepted: 09/22/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Receptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse. RESULTS High throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited. CONCLUSIONS This study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.
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Affiliation(s)
- Hon Yeung Chan
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Ha M Tran
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - James Breen
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - John E Schjenken
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, NSW, 2305, Australia
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
| | - Sarah A Robertson
- The Robinson Research Institute, School of Biomedicine, University of Adelaide, Adelaide, SA, 5000, Australia.
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20
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Zhong J, Qiu M, Meng Y, Wang P, Chen S, Wang L. Single-cell multi-omics sequencing reveals the immunological disturbance underlying STAT3-V637M Hyper-IgE syndrome. Int Immunopharmacol 2023; 122:110624. [PMID: 37480751 DOI: 10.1016/j.intimp.2023.110624] [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: 03/23/2023] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 07/24/2023]
Abstract
Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by, among others, the excessive production of IgE and repetitive bacterial/fungal infections. Mutations in STAT3, a transcription factor that orchestrates immune responses, may cause HIES, but the underlying mechanisms are not fully understood. Here, we used multi-omic approaches to comprehensively decipher the immune disturbance in a male HIES patient harboring STAT3-V637M. In his peripheral blood mononuclear cell (PBMC) we found significant clonal expansion of CD8 T cells (with increased CD8 subunits expression, potentially enhancing responsiveness to MHC I molecules), but not in his CD4 T cells and B cells. Although his B cells exhibited a higher potential in producing immunoglobulin, elevated SPIC binding might bias the products toward IgE isotype. Immune checkpoint inhibitors, including CTLA4, LAG3, were overexpressed in his PBMC-CD4 T cells, accompanied by reduced CD28 and IL6ST (gp130) expression. In his CD4 T cells, integrative analyses predicted upstream transcription factors (including ETV6, KLF13, and RORA) for LAG3, IL6ST, and CD28, respectively. The down-regulation of phagocytosis and nitric oxide synthesis-related genes in his PBMC-monocytes seem to be the culprit of his disseminated bacterial/fungal infection. Counterintuitively, in his PBMC we predicted increased STAT3 binding in both naïve and mature CD4 compartments, although this was not observed in most of his PBMC. In his bronchoalveolar lavage fluid (BALF), we found two macrophage subtypes with anti-bacterial properties, which were identified by CXCL8/S100A8/S100A9, or SOD2, respectively. Together, we described how the immune cell landscape was disturbed in STAT3-V637M HIES, providing a resource for further studies.
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Affiliation(s)
- Jiacheng Zhong
- Shenzhen Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital, Shenzhen 518055, Guangdong, China; Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518055, Guangdong, China
| | - Minzhi Qiu
- Health Management Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
| | - Yu Meng
- Department of Quality Control, Shenzhen People's Hospital, Shenzhen 518055, Guangdong, China
| | - Peizhong Wang
- Southern University of Science and Technology, Shenzhen 518055, Guangdong, China
| | - Shanze Chen
- Shenzhen Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital, Shenzhen 518055, Guangdong, China; Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518055, Guangdong, China.
| | - Lingwei Wang
- Shenzhen Institute of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital, Shenzhen 518055, Guangdong, China; Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518055, Guangdong, China.
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21
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Wang J, Zhao X, Wan YY. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol 2023; 20:1002-1022. [PMID: 37217798 PMCID: PMC10468540 DOI: 10.1038/s41423-023-01036-7] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Balanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
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Affiliation(s)
- Junying Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Xingqi Zhao
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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22
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Waldner MJ, Neurath MF. TGFβ and the Tumor Microenvironment in Colorectal Cancer. Cells 2023; 12:1139. [PMID: 37190048 PMCID: PMC10137236 DOI: 10.3390/cells12081139] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Growing evidence supports an important role of the tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC). Resident cells such as fibroblasts or immune cells infiltrating into the TME maintain continuous crosstalk with cancer cells and thereby regulate CRC progression. One of the most important molecules involved is the immunoregulatory cytokine transforming growth factor-β (TGFβ). TGFβ is released by various cells in the TME, including macrophages and fibroblasts, and it modulates cancer cell growth, differentiation, and cell death. Mutations in components of the TGF pathway, including TGFβ receptor type 2 or SMAD4, are among the most frequently detected mutations in CRC and have been associated with the clinical course of disease. Within this review, we will discuss our current understanding about the role of TGFβ in the pathogenesis of CRC. This includes novel data on the molecular mechanisms of TGFβ signaling in TME, as well as possible strategies for CRC therapy targeting the TGFβ pathway, including potential combinations with immune checkpoint inhibitors.
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Affiliation(s)
- Maximilian J. Waldner
- Department of Internal Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Internal Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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23
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El‐Husseini ZW, Vonk JM, van den Berge M, Gosens R, Koppelman GH. Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma. Clin Transl Allergy 2023; 13:e12239. [PMID: 37186423 PMCID: PMC10119226 DOI: 10.1002/clt2.12239] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/11/2023] [Accepted: 03/13/2023] [Indexed: 05/17/2023] Open
Abstract
INTRODUCTION Asthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome-wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma-associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma-associated traits and assess expression quantitative trait locus (e-QTLs) to reveal their downstream functional effects and find drug targets. METHODS Association analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population-based studies (Lifelines N = 32,817/Vlagtwedde-Vlaardingen N = 1554) and an asthma cohort (Dutch Asthma genome-wide association study N = 917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e-QTL analysis. Genes were investigated to generate novel drug targets. RESULTS We identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL-18, CCR4, and calcineurin. CONCLUSION Many asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma-associated traits were identified.
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Affiliation(s)
- Zaid W. El‐Husseini
- Department of Pediatric Pulmonology and Pediatric AllergologyBeatrix Children's HospitalUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC)University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Molecular PharmacologyGroningen Research Institute of PharmacyGroningenThe Netherlands
| | - Judith M. Vonk
- Groningen Research Institute for Asthma and COPD (GRIAC)University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Department of EpidemiologyUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Maarten van den Berge
- Groningen Research Institute for Asthma and COPD (GRIAC)University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Department of Pulmonary DiseasesUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - Reinoud Gosens
- Groningen Research Institute for Asthma and COPD (GRIAC)University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Molecular PharmacologyGroningen Research Institute of PharmacyGroningenThe Netherlands
| | - Gerard H. Koppelman
- Department of Pediatric Pulmonology and Pediatric AllergologyBeatrix Children's HospitalUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC)University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
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24
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Su QJ, Jiang H, Zhang Y, Huang LJ. SMAD2/3 Phosphorylation Is Downregulated in T Cells in HIV-Infected Patients. AIDS Res Hum Retroviruses 2023; 39:99-103. [PMID: 36226468 DOI: 10.1089/aid.2021.0212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Persistent inflammation contributes to the exhaustion of immune system and non-AIDS-defining events in HIV-infected patients. Transforming growth factor β (TGF-β) is generally considered an anti-inflammatory cytokine. It is unclear that why high-level TGF-β coexists with chronic inflammation during HIV infection. In this study, it was found that HIV-infected patients had lower proportion of phosphorylated SMAD2/3-positive cells among total CD3+ T cells and subsets of CD3+CD8+ and CD3+CD8- T cells when compared with health subjects. The findings implied that phosphorylation of SMAD2/3 is inhibited in HIV-infected patients, and that disturbance of TGF-β/SMAD2/3 signaling pathway may be involved in HIV-related chronic inflammation.
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Affiliation(s)
- Qi-Jian Su
- Department of Infectious Diseases, The First People's Hospital of Qinzhou/The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou, P.R. China
| | - Hui Jiang
- Department of Infectious Diseases, The First People's Hospital of Qinzhou/The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou, P.R. China
| | - Yu Zhang
- Department of Infectious Diseases, The First People's Hospital of Qinzhou/The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou, P.R. China
| | - Li-Jing Huang
- Department of Infectious Diseases, The First People's Hospital of Qinzhou/The Tenth Affiliated Hospital of Guangxi Medical University, Qinzhou, P.R. China
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25
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Parab S, Doshi G. The Experimental Animal Models in Psoriasis Research: A Comprehensive Review. Int Immunopharmacol 2023; 117:109897. [PMID: 36822099 DOI: 10.1016/j.intimp.2023.109897] [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: 12/08/2022] [Revised: 01/31/2023] [Accepted: 02/11/2023] [Indexed: 02/23/2023]
Abstract
Psoriasis is an autoimmune, chronic, inflammatory skin condition mediated by T cells. It differs from other inflammatory conditions by causing significant alterations in epidermal cell proliferation and differentiation that are both complicated and prominent. The lack of an appropriate animal model has significantly hindered studies into the pathogenic mechanisms of psoriasis since animals other than humans typically do not exhibit the complex phenotypic features of human psoriasis. A variety of methods, including spontaneous mutations, drug-induced mutations, genetically engineered animals, xenotransplantation models, and immunological reconstitution approaches, have all been employed to study specific characteristics in the pathogenesis of psoriasis. Although some of these approaches have been used for more than 50 years and far more models have been introduced recently, they have surprisingly not yet undergone detailed validation. Despite their limitations, these models have shown a connection between keratinocyte hyperplasia, vascular hyperplasia, and a cell-mediated immune response in the skin. The xenotransplantation of diseased or unaffected human skin onto immune-compromised recipients has also significantly aided psoriasis research. This technique has been used in a variety of ways to investigate the function of T lymphocytes and other cells, including preclinical therapeutic studies. The design of pertinent in vivo and in vitro psoriasis models is currently of utmost concern and a crucial step toward its cure. This article outlines the general approach in the development of psoriasis-related animal models, aspects of some specific models, along with their strengths and limitations.
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Affiliation(s)
- Siddhi Parab
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India
| | - Gaurav Doshi
- SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India.
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26
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Sun X, Xu X, Wang J, Zhang X, Zhao Z, Liu X, Wang G, Teng L, Chen X, Wang D, Li Y. Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells. Acta Pharm Sin B 2023. [PMID: 37521862 PMCID: PMC10373095 DOI: 10.1016/j.apsb.2023.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Deficiency of natural killer (NK) cells shows a significant impact on tumor progression and failure of immunotherapy. It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment. Unfortunately, mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors, thus declining antitumor efficiency. Herein, we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15 (IL-15). The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction, which provides a new methodology to trigger aggregation. It shows self-adaptive size-enlargement upon acidity, thus improving drug retention in tumor to over 120 h. The diameter of agglomerates is increased and drug release is effectively promoted following reduced pH values. The nanoparticles activate both NK cell and CD8+ T cell immunity in vivo. It significantly suppresses CT26 tumor in immune-deficient BALB/c mice, and the efficiency is further improved in immunocompetent mice, indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity. The approach reported here provides an innovative strategy to improve drug retention in tumors, which will enhance cancer immunotherapy by boosting NK cells.
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Jena SR, Nayak J, Kumar S, Kar S, Samanta L. Comparative proteome profiling of seminal components reveal impaired immune cell signalling as paternal contributors in recurrent pregnancy loss patients. Am J Reprod Immunol 2023; 89:e13613. [PMID: 35998016 DOI: 10.1111/aji.13613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 05/06/2022] [Accepted: 08/15/2022] [Indexed: 02/01/2023] Open
Abstract
PROBLEM Recurrent pregnancy loss (RPL) is usually evaluated from a women's perspective, however, recent evidence implies involvement of male factors as paternally expressed genes predominate placenta. During fertilization, prior to implantation the immune system purposefully produces early pregnancy factors with potent immunomodulatory properties for adaptation to antigenically dissimilar embryo. Therefore, it is hypothesized that paternal immunological factors play a role in RPL. METHOD OF STUDY Comparative proteome profiling (label free liquid chromatography mass spectroscopy: LC-MS/MS) of the seminal extracellular vesicles (SEVs), extracellular vesicle free seminal plasma (EVF-SP) and spermatozoa was carried out in semen of RPL patients (n = 21) and fertile donors (n = 21). This was followed by pathway and protein-protein interaction analysis, and validation of key proteins' expression (western blot). RESULTS A total of 68, 28 and 49 differentially expressed proteins in SEVs, EVF-SP and spermatozoa of RPL patients, respectively, were found to be involved in inflammatory response, immune cell signalling and apoptosis. In SEVs, underexpressed GDF-15 and overexpressed C3 imply distorted maternal immune response to paternal antigens leading to impaired decidualization. Dysregulated TGFβ signalling in EVF-SP surmises defective modulation of inflammatory response and induction of immune tolerance to seminal antigens in the female reproductive tract through generation of regulatory T cells. Retained histone variants in spermatozoa construe defective expression of early paternal genes, while underexpressed PTN may inflict defective angiogenesis resulting in expulsion of decidua. CONCLUSIONS Impaired modulation of immune response and improper placental development due to altered cytokine levels in seminal components may be the contributing paternal factors in RPL.
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Affiliation(s)
- Soumya Ranjan Jena
- Redox Biology & Proteomics Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, College Square, Cuttack, Odisha, India.,Centre of Excellence in Environment and Public Health, Ravenshaw University, College Square, Cuttack, Odisha, India
| | - Jasmine Nayak
- Redox Biology & Proteomics Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, College Square, Cuttack, Odisha, India.,Centre of Excellence in Environment and Public Health, Ravenshaw University, College Square, Cuttack, Odisha, India
| | - Sugandh Kumar
- School of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Sujata Kar
- Department of Obstetrics & Gynaecology, Kar Clinic and Hospital Pvt. Ltd., Bhubaneswar, India
| | - Luna Samanta
- Redox Biology & Proteomics Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, College Square, Cuttack, Odisha, India.,Centre of Excellence in Environment and Public Health, Ravenshaw University, College Square, Cuttack, Odisha, India
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28
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Rana PS, Soler DC, Kort J, Driscoll JJ. Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction. Front Cell Dev Biol 2022; 10:1059715. [PMID: 36578789 PMCID: PMC9790996 DOI: 10.3389/fcell.2022.1059715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) remains a lethal hematologic cancer characterized by the expansion of transformed plasma cells within the permissive bone marrow (BM) milieu. The emergence of relapsed and/or refractory MM (RRMM) is provoked through clonal evolution of malignant plasma cells that harbor genomic, metabolic and proteomic perturbations. For most patients, relapsed disease remains a major cause of overall mortality. Transforming growth factors (TGFs) have pleiotropic effects that regulate myelomagenesis as well as the emergence of drug resistance. Moreover, TGF-β modulates numerous cell types present with the tumor microenvironment, including many immune cell types. While numerous agents have been FDA-approved over the past 2 decades and significantly expanded the treatment options available for MM patients, the molecular mechanisms responsible for drug resistance remain elusive. Multiple myeloma is uniformly preceded by a premalignant state, monoclonal gammopathy of unknown significance, and both conditions are associated with progressive deregulation in host immunity characterized by reduced T cell, natural killer (NK) cell and antigen-presenting dendritic cell (DC) activity. TGF-β promotes myelomagenesis as well as intrinsic drug resistance by repressing anti-myeloma immunity to promote tolerance, drug resistance and disease progression. Hence, repression of TGF-β signaling is a prerequisite to enhance the efficacy of current and future immunotherapeutics. Novel strategies that incorporate T cells that have been modified to express chimeric antigen receptor (CARs), T cell receptors (TCRs) and bispecific T cell engagers (BiTEs) offer promise to block TGF-β signaling, overcome chemoresistance and enhance anti-myeloma immunity. Here, we describe the effects of TGF-β signaling on immune cell effectors in the bone marrow and emerging strategies to overcome TGF-β-mediated myeloma growth, drug resistance and survival.
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Affiliation(s)
- Priyanka S. Rana
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States
| | - David C. Soler
- The Brain Tumor and Neuro-Oncology Center, The Center of Excellence for Translational Neuro-Oncology, Department of Neurosurgery, Case Western Reserve University, Cleveland, OH, United States
| | - Jeries Kort
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States,Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - James J. Driscoll
- Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, United States,Case Comprehensive Cancer Center, Cleveland, OH, United States,Adult Hematologic Malignancies and Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, United States,*Correspondence: James J. Driscoll,
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29
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Li S, Zong X, Zhang L, Li L, Wu J. A chromatin accessibility landscape during early adipogenesis of human adipose-derived stem cells. Adipocyte 2022; 11:239-249. [PMID: 35435105 PMCID: PMC9037556 DOI: 10.1080/21623945.2022.2063015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Obesity has become a serious global public health problem; a deeper understanding of systemic change of chromatin accessibility during human adipogenesis contributes to conquering obesity and its related diseases. Here, we applied the ATAC-seq method to depict a high-quality genome‐wide time-resolved accessible chromatin atlas during adipogenesis of human adipose-derived stem cells (hASCs). Our data indicated that the chromatin accessibility drastic dynamically reformed during the adipogenesis of hASCs and 8 h may be the critical transition node of adipogenesis chromatin states from commitment phase to determination phase. Moreover, upon adipogenesis, we also found that the chromatin accessibility of regions related to anti-apoptotic, angiogenic and immunoregulatory gradually increased, which is beneficial to maintaining the health of adipose tissue (AT). Finally, the chromatin accessibility changed significantly in intronic regions of peroxisome proliferator‐activated receptor γ during adipogenesis, and these regions were rich in transcription factors binding motifs that were exposed for further regulation. Overall, we systematically analysed the complex change of chromatin accessibility occurring in the early stage of adipogenesis and deepened our understanding of human adipogenesis. Furthermore, we also provided a good reference data resource of genome‐wide chromatin accessibility for future studies on human adipogenesis.
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Affiliation(s)
- Sen Li
- Department of Biochemistry & Immunology, Capital Institute of Pediatrics, Beijing, China
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Xiaolin Zong
- Division of achievements transformation, Development Center for Medical Science & Technology National Health Commission of the People’s Republic of China, Beijing, China
| | - Liheng Zhang
- Shanghai Jiayin Biotechnology Co., Ltd, Shanghai, China
| | - Luya Li
- Department of Biochemistry & Immunology, Capital Institute of Pediatrics, Beijing, China
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Jianxin Wu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
- Beijing TongRen Hospital, Capital Medical University, Beijing, China
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30
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Raza GS, Sodum N, Kaya Y, Herzig KH. Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis. Int J Mol Sci 2022; 23:12954. [PMID: 36361737 PMCID: PMC9655416 DOI: 10.3390/ijms232112954] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 09/12/2023] Open
Abstract
Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.
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Affiliation(s)
- Ghulam Shere Raza
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Nalini Sodum
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Yagmur Kaya
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Marmara University, 34854 Istanbul, Turkey
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
- Oulu University Hospital, University of Oulu, 90220 Oulu, Finland
- Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, 60-572 Poznań, Poland
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31
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Schuler C, Foti F, Perren L, Mamie C, Weder B, Stokmaier M, de Vallière C, Heuchel R, Ruiz PA, Rogler G, Hausmann M. Deletion of Smad7 Ameliorates Intestinal Inflammation and Contributes to Fibrosis. Inflamm Bowel Dis 2022; 29:647-660. [PMID: 36282601 DOI: 10.1093/ibd/izac221] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of transforming growth factor (TGF)-β compared with non-IBD controls. SMAD7 negatively regulates TGF-β signaling. An earlier study aiming to target Smad7 showed a lack of clinical benefit. It remains unknown whether inhibition of SMAD7 is beneficial in specific settings of IBD. We evaluated the effect of Smad7 deficiency on inflammation, fibrogenesis, and wound healing. METHODS For the initiation of fibrosis in Smad7-/- (Smad7Δex-I) CD-1 mice, the dextran sodium sulfate-induced chronic colitis model and the heterotopic transplantation model of fibrosis were used. Wound closure of fibroblasts from Smad7-/- mice was determined using culture inserts and electric cell-substrate impedance sensing in vitro. RESULTS In dextran sodium sulfate-induced chronic colitis, Smad7 deficiency was associated with ameliorated inflammation, as evidenced by decreased clinical score, histological score, and myeloperoxidase activity. Absence of SMAD7 decreased T-cell accumulation in colonic tissue and tumor necrosis factor (TNF) mRNA expression levels. Smad7-/- mice showed a significant increase in hydroxyproline and collagen content, as well as ColIVa1 mRNA expression. Wild type mice transplanted with terminal ileum from Smad7-/- mice in the heterotopic animal model for intestinal fibrosis showed a significant increase in collagen content and protein expression of α-smooth muscle actin. CONCLUSIONS Smad7 deficiency is associated with a decrease in intestinal inflammation and an increase in fibrosis. Targeting SMAD7 constitutes a potential new treatment option for IBD; progression of disease-associated fibrosis should be considered.
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Affiliation(s)
- Cordelia Schuler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Federica Foti
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Leonie Perren
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Michelle Stokmaier
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Rainer Heuchel
- Pancreas Cancer Research Lab, CLINTEC, Karolinska Institutet, Huddinge, Sweden
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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Freitas NL, Gomes YCP, Souza FDS, Torres RC, Echevarria-Lima J, Leite ACCB, Lima MASD, Araújo AQC, Silva MTT, Espíndola ODM. Lessons from the Cerebrospinal Fluid Analysis of HTLV-1-Infected Individuals: Biomarkers of Inflammation for HAM/TSP Development. Viruses 2022; 14:v14102146. [PMID: 36298702 PMCID: PMC9609689 DOI: 10.3390/v14102146] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/23/2022] [Accepted: 09/27/2022] [Indexed: 11/18/2022] Open
Abstract
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, β-NGF, TGF-β1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin <1 and of CXCL10 < 2). HAM/TSP patients with normal CSF levels of neurofilament light chain (NfL) showed elevated β-NGF in serum, and serum BDNF levels were increased in HTLV-1-infected individuals, particularly in HTLV-1 AC. Both HTLV-1 AC and HAM/TSP patients had lower TGF-β1 levels in CSF compared to uninfected individuals, and HAM/TSP patients with active CNS inflammation showed higher CSF levels of IL-18, which correlated with markers of inflammation, neuronal death, and blood−brain-barrier permeability. Although none of the factors evaluated were associated with the speed of HAM/TSP progression, reduced TGF-β1 levels in CSF suggest that suppressive responses to control subclinical and/or active neurodegeneration are impaired, while increased CSF IL-18 indicates the involvement of inflammasome-mediated mechanisms in HAM/TSP development.
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Affiliation(s)
- Nicole Lardini Freitas
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Yago Côrtes Pinheiro Gomes
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
- Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Flávia dos Santos Souza
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Rafael Carvalho Torres
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil
- Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-912, Brazil
| | - Juliana Echevarria-Lima
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil
| | | | | | - Abelardo Queiroz Campos Araújo
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Marcus Tulius Teixeira Silva
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Otávio de Melo Espíndola
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
- Correspondence:
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33
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Free SR, Carraway KL. Platelets in Hematogenous Breast Cancer Metastasis: Partners in Crime. Breast Cancer 2022. [DOI: 10.36255/exon-publications-breast-cancer-platelets] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Wu S, Xu Y, Zhang J, Ran X, Jia X, Wang J, Sun L, Yang H, Li Y, Fu B, Huang C, Liao P, Sun W. Longitudinal Serum Proteome Characterization of COVID-19 Patients With Different Severities Revealed Potential Therapeutic Strategies. Front Immunol 2022; 13:893943. [PMID: 35958562 PMCID: PMC9361788 DOI: 10.3389/fimmu.2022.893943] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/21/2022] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 is exerting huge pressure on global healthcare. Understanding of the molecular pathophysiological alterations in COVID-19 patients with different severities during disease is important for effective treatment. In this study, we performed proteomic profiling of 181 serum samples collected at multiple time points from 79 COVID-19 patients with different severity levels (asymptomatic, mild, moderate, and severe/critical) and 27 serum samples from non-COVID-19 control individuals. Dysregulation of immune response and metabolic reprogramming was found in severe/critical COVID-19 patients compared with non-severe/critical patients, whereas asymptomatic patients presented an effective immune response compared with symptomatic COVID-19 patients. Interestingly, the moderate COVID-19 patients were mainly grouped into two distinct clusters using hierarchical cluster analysis, which demonstrates the molecular pathophysiological heterogeneity in COVID-19 patients. Analysis of protein-level alterations during disease progression revealed that proteins involved in complement activation, the coagulation cascade and cholesterol metabolism were restored at the convalescence stage, but the levels of some proteins, such as anti-angiogenesis protein PLGLB1, would not recovered. The higher serum level of PLGLB1 in COVID-19 patients than in control groups was further confirmed by parallel reaction monitoring (PRM). These findings expand our understanding of the pathogenesis and progression of COVID-19 and provide insight into the discovery of potential therapeutic targets and serum biomarkers worth further validation.
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Affiliation(s)
- Songfeng Wu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yuan Xu
- Department of Clinical Laboratory, Chongqing General Hospital, Chongqing, China
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Chongqing Medical University, Chongqing, China
| | - Jian Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xiaoju Ran
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xue Jia
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Jing Wang
- Department of Clinical Laboratory, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing, China
| | - Longqin Sun
- Beijing Qinglian Biotech Co., Ltd, Beijing, China
| | - Huan Yang
- Department of Clinical Laboratory, Chongqing General Hospital, Chongqing, China
- School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yulei Li
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Bin Fu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Changwu Huang
- Department of Clinical Laboratory, Chongqing Fifth People’s Hospital, Chongqing, China
- *Correspondence: Wei Sun, ; Pu Liao, ; Changwu Huang,
| | - Pu Liao
- Department of Clinical Laboratory, Chongqing General Hospital, Chongqing, China
- *Correspondence: Wei Sun, ; Pu Liao, ; Changwu Huang,
| | - Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
- *Correspondence: Wei Sun, ; Pu Liao, ; Changwu Huang,
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35
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Zhang Q, Yang Y, Chen Y, Wang Y, Qin S, Lv R, Zhou M, Yu Q, Li X, Li X, Wang X, You H, Wang Y, Zhou F, Liu X. The LncRNA AK018453 regulates TRAP1/Smad signaling in IL-17-activated astrocytes: A potential role in EAE pathogenesis. Glia 2022; 70:2079-2092. [PMID: 35778934 PMCID: PMC9545958 DOI: 10.1002/glia.24239] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/11/2022]
Abstract
The pro-inflammatory cytokine interleukin 17 (IL-17), that is mainly produced by Th17 cells, has been recognized as a key regulator in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Reactive astrocytes stimulated by proinflammatory cytokines including IL-17 are involved in blood brain barrier destruction, inflammatory cells infiltration and spinal cord injury. However, the role of long non-coding RNAs (lncRNAs) induced by IL-17 in the pathogenesis of MS and EAE remains unknown. Herein, we found that an IL-17-induced lncRNA AK018453 promoted TGF-β receptor-associated protein 1 (TRAP1) expression and Smad-dependent signaling in mouse primary astrocytes. Knockdown of AK018453 significantly suppressed astrocytosis, attenuated the phosphorylation of Smad2/3, reduced NF-κB p65 and CBP/P300 binding to the TRAP1 promoter, and diminished pro-inflammatory cytokine production in the IL-17-treated astrocytes. AK018453 knockdown in astrocytes by a lentiviral vector in vivo dramatically inhibited inflammation and prevented the mice from demyelination in the spinal cord during the progression of EAE. Together, these results suggest that AK018453 regulates IL-17-dependent inflammatory response in reactive astrocytes and potentially promotes the pathogenesis of EAE via the TRAP1/Smad pathway. Targeting this pathway may have a therapeutic potential for intervening inflammatory demyelinating diseases.
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Affiliation(s)
- Qingxiu Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.,Department of Neurology, Nanjing Drum Tower Clinical College of Xuzhou Medical University, Nanjing, China
| | - Ying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yingyu Chen
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yifan Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Suping Qin
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ruixue Lv
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Menglu Zhou
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qian Yu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiangyang Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaotian Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yugang Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Feng Zhou
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaomei Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu, China
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Li F, Long Y, Yu X, Tong Y, Gong L. Different Immunoregulation Roles of Activin A Compared With TGF-β. Front Immunol 2022; 13:921366. [PMID: 35774793 PMCID: PMC9237220 DOI: 10.3389/fimmu.2022.921366] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Activin A, a critical member of the transforming growth factor-β (TGF-β) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and other diseases with immune disorder. Similar to its family member, TGF-β, activin A also transmits signals through SMAD2/SMAD3, however, they bind to distinct receptors. Recent studies have uncovered that activin A plays a pivotal role in both innate and adaptive immune systems. Here we mainly focus its effects on activation, differentiation, proliferation and function of cells which are indispensable in the immune system and meanwhile make some comparisons with those of TGF-β.
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Affiliation(s)
- Fanglin Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yiru Long
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaolu Yu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongliang Tong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Likun Gong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China
- *Correspondence: Likun Gong,
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Gao TA, Chen YY. Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism. Annu Rev Chem Biomol Eng 2022; 13:193-216. [PMID: 35700528 DOI: 10.1146/annurev-chembioeng-092120-092914] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
T cells engineered to express chimeric antigen receptors (CARs) have shown remarkable success in treating B-cell malignancies, reflected by multiple US Food and Drug Administration-approved CAR-T cell products currently on the market. However, various obstacles have thus far limited the use of approved products and constrained the efficacy of CAR-T cell therapy against solid tumors. Overcoming these obstacles will necessitate multidimensional CAR-T cell engineering approaches and better understanding of the intricate tumor microenvironment (TME). Key challenges include treatment-related toxicity, antigen escape and heterogeneity, and the highly immunosuppressive profile of the TME. Notably, the hypoxic and nutrient-deprived nature of the TME severely attenuates CAR-T cell fitness and efficacy, highlighting the need for more sophisticated engineering strategies. In this review, we examine recent advances in protein- and cell-engineering strategies to improve CAR-T cell safety and efficacy, with an emphasis on overcoming immunosuppression induced by tumor metabolism and hypoxia.
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Affiliation(s)
- Torahito A Gao
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA; ,
| | - Yvonne Y Chen
- Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA; , .,Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.,Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, California, USA
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Detection of Specific Immune Cell Subpopulation Changes Associated with Systemic Immune Inflammation–Index Level in Germ Cell Tumors. Life (Basel) 2022; 12:life12050678. [PMID: 35629346 PMCID: PMC9147028 DOI: 10.3390/life12050678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 11/21/2022] Open
Abstract
The tumor microenvironment (TME) and the host inflammatory response are closely interconnected. The interplay between systemic inflammation and the local immune response may influence tumor development and progression in various types of cancer. The systemic immune–inflammation index (SII) represents a prognostic marker for germ cell tumors (GCTs). The aim of the present study was to detect specific immune cell subpopulation changes which were associated with the SII level in chemotherapy-naïve GCT patients. In total, 51 GCT patients, prior to cisplatin-based chemotherapy, were included in the present study. Immunophenotyping of peripheral blood leukocyte subpopulations was performed using flow cytometry. The SII level was correlated with the percentage of various leukocyte subpopulations. The obtained results demonstrated that SII levels above the cut-off value of SII ≥ 1003 were associated with higher neutrophil percentages. An inverse correlation was found between the SII and the peripheral lymphocyte percentage that logically reflects the calculations of the SII index. Furthermore, the presented data also showed that in the lymphocyte subpopulation, the association with the SII was driven by T-cell subpopulations. In innate immunity–cell subpopulations, we observed a correlation between SII level and neutrophils as well as associations with eosinophil, basophil, natural killer cell and dendritic cell percentages. We suppose that the described interactions represent a manifestation of cancer-induced immune suppression. The results of the present study contribute to the elucidation of the interrelationship between tumor cells and the innate/adaptive immune system of the host.
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39
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Li Y, Ji H, Gao X. A 2-Gene Signature Related to Interferon-Gamma Predicts Prognosis and Responsiveness to Immune Checkpoint Blockade of Glioma. Front Med (Lausanne) 2022; 9:846847. [PMID: 35492352 PMCID: PMC9051065 DOI: 10.3389/fmed.2022.846847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundGliomas represent the most common and aggressive brain malignancy. Interferon-gamma (IFNG) is a potent inducer of immune response, developing IFNG-related gene signature may promote the diagnosis and treatment of this disease.MethodsBulk tumor and single-cell mRNA-seq datasets of glioma ranging from WHO grade II to IV with corresponding demographics were included. Multiple bioinformatics and machine learning algorithms were performed to develop an IFNG-related prognostic signature and evaluate immune checkpoint blockade (ICB) therapy response.ResultsIFNGR1 and IFNGR2 were used as concise IFNG-related gene signature based on which the IFNGR score well-characterized the IFNG response in the glioma microenvironment. Increased IFNGR score was associated with clinicopathological parameters relating to tumor malignancy and prevailing molecular pathological markers. Notably, K-M and Cox regression analysis found that the IFNGR score was an effective prognostic biomarker, and was associated with tumor relapse for a subset of patients. Notably, IFNGR1 and IFNGR2 were preferentially expressed by the Mono/Macro cells in the glioma microenvironment and were significantly correlated with M2 macrophage. Thus, the IFNGR score-high group had increased expression of immune checkpoints and had the potential to predict ICB responsiveness.ConclusionIn conclusion, we have developed a concise IFNG-related gene signature of clinical significance, which may improve the current diagnosis and treatment of glioma.
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Affiliation(s)
- Yongzhe Li
- Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Yongzhe Li
| | - Hang Ji
- Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Xin Gao
- Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
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40
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Simsek H, Klotzsch E. The solid tumor microenvironment-Breaking the barrier for T cells: How the solid tumor microenvironment influences T cells: How the solid tumor microenvironment influences T cells. Bioessays 2022; 44:e2100285. [PMID: 35393714 DOI: 10.1002/bies.202100285] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/20/2022]
Abstract
The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies.
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Affiliation(s)
- Hasan Simsek
- Institute for Biology, Experimental Biophysics/Mechanobiology, Humboldt University of Berlin, Berlin, Germany
| | - Enrico Klotzsch
- Institute for Biology, Experimental Biophysics/Mechanobiology, Humboldt University of Berlin, Berlin, Germany.,Laboratory of Applied Mechanobiology, Department for Health Sciences and Technology, ETH Zürich, Zürich, Switzerland
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41
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Tackling the effects of extracellular vesicles in fibrosis. Eur J Cell Biol 2022; 101:151221. [PMID: 35405464 DOI: 10.1016/j.ejcb.2022.151221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022] Open
Abstract
Fibrosis is a physiological process of tissue repair that turns into pathological when becomes chronic, damaging the functional structure of the tissue. In this review we outline the current status of extracellular vesicles as modulators of the fibrotic process at different levels. In adipose tissue, extracellular vesicles mediate the intercellular communication not only between adipocytes, but also between adipocytes and other cells of the stromal vascular fraction. Thus, they could be altering essential processes for the functionality of adipose tissue, such as adipocyte hypertrophy/hyperplasia, tissue plasticity, adipogenesis and/or inflammation, and ultimately trigger fibrosis. This process is particularly important in obesity, and may eventually, influence the development of obesity-associated alterations. In this regard, obesity is now recognized as an independent risk factor for the development of chronic kidney disease, although the role of extracellular vesicles in this connection has not been explored so far. Nonetheless, the role of extracellular vesicles in the onset and progression of renal fibrosis has been highlighted due to the critical role of fibrosis as a common feature of kidney diseases. In fact, the content of extracellular vesicles disturbs cellular signaling cascades involved in fibrosis in virtually all types of renal cells. What is certain is that the study of extracellular vesicles is complex, as their isolation and manipulation is still difficult to reproduce, which complicates the overview of their physiopathological effects. Nevertheless, new strategies have been developed to exploit the potential of extracellular vesicles and their cargo, both as biomarkers and as therapeutic tools to prevent the progression of fibrosis towards an irreversible event.
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42
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Luther JM, Fogo AB. The role of mineralocorticoid receptor activation in kidney inflammation and fibrosis. Kidney Int Suppl (2011) 2022; 12:63-68. [DOI: 10.1016/j.kisu.2021.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/15/2021] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
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Second Cancer Onset in Myeloproliferative Neoplasms: What, When, Why? Int J Mol Sci 2022; 23:ijms23063177. [PMID: 35328597 PMCID: PMC8954627 DOI: 10.3390/ijms23063177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/12/2022] [Accepted: 03/14/2022] [Indexed: 11/18/2022] Open
Abstract
The risk of developing a solid cancer is a major issue arising in the disease course of a myeloproliferative neoplasm (MPN). Although the connection between the two diseases has been widely described, the backstage of this complex scenario has still to be explored. Several cellular and molecular mechanisms have been suggested to link the two tumors. Sometimes the MPN is considered to trigger a second cancer but at other times both diseases seem to depend on the same source. Increasing knowledge in recent years has revealed emerging pathways, supporting older, more consolidated theories, but there are still many unresolved issues. Our work aims to present the biological face of the complex clinical scenario in MPN patients developing a second cancer, focusing on the main cellular and molecular pathways linking the two diseases.
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44
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Hosseini R, Sarvnaz H, Arabpour M, Ramshe SM, Asef-Kabiri L, Yousefi H, Akbari ME, Eskandari N. Cancer exosomes and natural killer cells dysfunction: biological roles, clinical significance and implications for immunotherapy. Mol Cancer 2022; 21:15. [PMID: 35031075 PMCID: PMC8759167 DOI: 10.1186/s12943-021-01492-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/26/2021] [Indexed: 12/16/2022] Open
Abstract
Tumor-derived exosomes (TDEs) play pivotal roles in several aspects of cancer biology. It is now evident that TDEs also favor tumor growth by negatively affecting anti-tumor immunity. As important sentinels of immune surveillance system, natural killer (NK) cells can recognize malignant cells very early and counteract the tumor development and metastasis without a need for additional activation. Based on this rationale, adoptive transfer of ex vivo expanded NK cells/NK cell lines, such as NK-92 cells, has attracted great attention and is widely studied as a promising immunotherapy for cancer treatment. However, by exploiting various strategies, including secretion of exosomes, cancer cells are able to subvert NK cell responses. This paper reviews the roles of TDEs in cancer-induced NK cells impairments with mechanistic insights. The clinical significance and potential approaches to nullify the effects of TDEs on NK cells in cancer immunotherapy are also discussed.
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Affiliation(s)
- Reza Hosseini
- Department of Immunology School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Hamzeh Sarvnaz
- Department of Immunology School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maedeh Arabpour
- Department of Medical Genetics School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Molaei Ramshe
- Student Research Committee, Department of Medical Genetics, School of Medicine Shahid, Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Asef-Kabiri
- Surgical Oncologist Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, USA
| | - Mohammad Esmaeil Akbari
- Surgical Oncologist Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nahid Eskandari
- Department of Immunology School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Dong Z, Liao Z, He Y, Wu C, Meng Z, Qin B, Xu G, Li Z, Sun T, Wen Y, Li G. Advances in the Biological Functions and Mechanisms of miRNAs in the Development of Osteosarcoma. Technol Cancer Res Treat 2022; 21:15330338221117386. [PMID: 35950243 PMCID: PMC9379803 DOI: 10.1177/15330338221117386] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Osteosarcoma is one of the most common primary malignant bone tumors, mainly
occurring in children and adolescents, and is characterized by high morbidity
and poor prognosis. MicroRNAs, a class of noncoding RNAs consisting of 19 to 25
nucleotides, are involved in cell proliferation, invasion, metastasis, and
apoptosis to regulate the development and progression of osteosarcoma. Studies
have found that microRNAs are closely related to the diagnosis, treatment, and
prognosis of osteosarcoma patients and have an important role in improving drug
resistance in osteosarcoma. This paper reviews the role of microRNAs in the
pathogenesis of osteosarcoma and their clinical value, aiming to provide a new
research direction for diagnosing and treating osteosarcoma and achieving a
better prognosis.
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Affiliation(s)
- Zihe Dong
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zhipeng Liao
- The Second School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Yonglin He
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Chengye Wu
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zixiang Meng
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Baolong Qin
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Ge Xu
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zeyang Li
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Tianxin Sun
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Yuyan Wen
- The First School of Clinical Medicine, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Guangjie Li
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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The Effects of Sishen Wan on T Cell Responses in Mice Models of Ulcerative Colitis Induced by Dextran Sodium Sulfate. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9957709. [PMID: 34956391 PMCID: PMC8702314 DOI: 10.1155/2021/9957709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 12/24/2022]
Abstract
Currently, it is unclear whether Sishen Wan (SSW) could modulate the balance of Th1 cells, Th17 cells, and Tregs and we evaluated the effects of SSW on T cell responses in mice models of ulcerative colitis (UC). The mice models of acute UC (4% dextran sodium sulfate (DSS), 8 days) and chronic UC (3% DSS, 16 days) with SSW were assayed. Colon tissues were collected for immunohistochemical analysis, enzyme linked immunosorbent assay (ELISA), and flow cytometry (FCM). The expressions of cytokines associated with Tregs, transcription factors of Th17 cells, the frequencies of Th1 cells, Th17 cells, and Tregs, and the functional plasticity of Th17 cells were detected. The frequency of IFN-γ+ T cells was not changed significantly with SSW treatment in acute DSS. In chronic models, the frequency of IFN-γ+ T cells was downregulated with SSW. Meanwhile, the levels of RORγt and the frequency of IL-17A+ Th17 cells showed no significant differences after SSW treatment. Despite no significant effect on the transdifferentiation of Th17 cells in chronic UC models, SSW transdifferentiated Th17 cells into IL-10+ Th17 cells and downregulated IFN-γ+ Th17 cells/IL-10+ Th17 cells in acute DSS. Moreover, there were no significant changes of cytokines secreted by Tregs in acute DSS after SSW treatment, but SSW facilitated the expressions of IL-10 and IL-35, as well as development of IL-10+ Tregs in chronic DSS. SSW showed depressive effects on the immunoreaction of Th17 cells and might promote the conversion of Th17 cells into IL-10+ Th17 cells in acute UC, while it inhibited the excessive reaction of Th1 cells, facilitated the development of Tregs, and enhanced the anti-inflammatory effects in chronic UC.
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47
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Masoumi E, Tahaghoghi-Hajghorbani S, Jafarzadeh L, Sanaei MJ, Pourbagheri-Sigaroodi A, Bashash D. The application of immune checkpoint blockade in breast cancer and the emerging role of nanoparticle. J Control Release 2021; 340:168-187. [PMID: 34743998 DOI: 10.1016/j.jconrel.2021.10.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022]
Abstract
Breast cancer is the most common malignancy in the female population with a high mortality rate. Despite the satisfying depth of studies evaluating the contributory role of immune checkpoints in this malignancy, few articles have reviewed the pros and cons of immune checkpoint blockades (ICBs). In the current review, we provide an overview of immune-related inhibitory molecules and also discuss the original data obtained from international research laboratories on the aberrant expression of T and non-T cell-associated immune checkpoints in breast cancer. Then, we especially focus on recent studies that utilized ICBs as the treatment strategy in breast cancer and provide their efficiency reports. As there are always costs and benefits, we discuss the limitations and challenges toward ICB therapy such as adverse events and drug resistance. In the last section, we allocate an overview of the recent data concerning the application of nanoparticle systems for cancer immunotherapy and propose that nano-based ICB approaches may overcome the challenges related to ICB therapy in breast cancer. In conclusion, it seems it is time for nanoscience to more rapidly move forward into clinical trials and illuminates the breast cancer treatment area with its potent features for the target delivery of ICBs.
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Affiliation(s)
- Elham Masoumi
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran; Student Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Sahar Tahaghoghi-Hajghorbani
- Microbiology and Virology Research Center, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Leila Jafarzadeh
- Department of Laboratory Science, Sirjan Faculty of Medical Science, Sirjan, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wandmacher AM, Mehdorn AS, Sebens S. The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer. Cancers (Basel) 2021; 13:4932. [PMID: 34638420 PMCID: PMC8508450 DOI: 10.3390/cancers13194932] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/14/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.
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Affiliation(s)
| | - Anna Maxi Wandmacher
- Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany;
| | - Anne-Sophie Mehdorn
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany;
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building U30 Entrance 1, 24105 Kiel, Germany
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49
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He S, Li J, Cheng P, Zeng Z, Zhang C, Duan H, Pu K. Charge‐Reversal Polymer Nano‐modulators for Photodynamic Immunotherapy of Cancer. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202106392] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Shasha He
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Jingchao Li
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Penghui Cheng
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Ziling Zeng
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Chi Zhang
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Hongwei Duan
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
| | - Kanyi Pu
- School of Chemical and Biomedical Engineering School of Physical and Mathematical Sciences Nanyang Technological University 70 Nanyang Drive Singapore 637457 Singapore
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50
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Gough NR, Xiang X, Mishra L. TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer. Gastroenterology 2021; 161:434-452.e15. [PMID: 33940008 PMCID: PMC8841117 DOI: 10.1053/j.gastro.2021.04.064] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/05/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023]
Abstract
Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.
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Affiliation(s)
- Nancy R. Gough
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York; Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, District of Columbia.
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