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Hillmann J, Maass N, Bauerschlag DO, Flörkemeier I. Promising new drugs and therapeutic approaches for treatment of ovarian cancer-targeting the hallmarks of cancer. BMC Med 2025; 23:10. [PMID: 39762846 PMCID: PMC11706140 DOI: 10.1186/s12916-024-03826-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment.
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Affiliation(s)
- Julia Hillmann
- Department of Gynaecology and Obstetrics, University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Nicolai Maass
- Department of Gynaecology and Obstetrics, University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Dirk O Bauerschlag
- Department of Gynaecology and Obstetrics, University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
- Department of Gynaecology, Jena University Hospital, Jena, Germany.
| | - Inken Flörkemeier
- Department of Gynaecology and Obstetrics, University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
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Kwok TY, Hui RWH, Mao X, Ling GS, Wong DKH, Huang FY, Fung J, Seto WK, Yuen MF, Mak LY. Cigarette Smoking Is Associated With Lower Chance of Hepatitis B Surface Antigen Seroclearance and Altered Host Immunity. J Viral Hepat 2024; 31:847-856. [PMID: 39248338 DOI: 10.1111/jvh.14007] [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: 06/16/2024] [Revised: 08/12/2024] [Accepted: 08/25/2024] [Indexed: 09/10/2024]
Abstract
Cigarette smoking is associated with worse clinical outcomes in patients with chronic hepatitis B (CHB) infection, but the effects on hepatitis B surface antigen (HBsAg) seroclearance are unclear. This study aimed to investigate the effect of active smoking on HBsAg seroclearance (SC) and its impact on peripheral blood lymphocytes in patients with CHB infection. Longitudinal follow-up data was retrieved in 7833 antiviral-treated CHB subjects identified from a centralised electronic patient record database (Part 1). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) from 27 CHB-infected patients (6 active smokers; 13 with SC) was performed by flow cytometry to assess programmed death-1 (PD-1) expression and proportion of regulatory T cells (CD4+CD25+CD127lo). Effector function of HBV-specific T cells was examined by comparing granzyme B (GZMB) and transforming growth factor beta (TGFβ) production in undepleted PBMCs and Treg-depleted PBMCs after 7 days in vitro stimulation with HBV envelope protein overlapping peptides (Part 2). Over a median follow-up of 5 years, smoking was associated with lower probability of SC (aHR 0.70, 95% CI 0.57-0.87). PD-1 expression was increased in CD4+ T cells, CD8+ T cells and CD20+ B cells among smokers compared to non-smokers and positively correlated with pack years (all p < 0.05). Treg depletion led to partial functional recovery of HBV-specific T cells, with significantly bigger magnitude in smokers (p = 0.0451, mean difference = 4.68%) than non-smokers (p = 0.012, mean difference = 4.2%). Cigarette smoking is associated with lower chance of HBsAg seroclearance, higher PD-1 expression on lymphocytes, and impairment of effector functions of HBV-specific T cells in CHB.
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Affiliation(s)
- Tsz-Yan Kwok
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - XianHua Mao
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Guang-Sheng Ling
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Fung-Yu Huang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Pednekar K, Minnee J, de Vries IJM, Prakash J. Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside. Eur J Pharm Biopharm 2024; 204:114510. [PMID: 39307440 DOI: 10.1016/j.ejpb.2024.114510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/13/2024] [Accepted: 09/20/2024] [Indexed: 10/27/2024]
Abstract
Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.
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Affiliation(s)
- Kunal Pednekar
- Engineered Therapeutics, Department of Advanced Organ bioengineering and Therapeutics, Technical Medical Centre, University of Twente, Enschede, The Netherlands
| | - Julia Minnee
- Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, The Netherlands
| | - I Jolanda M de Vries
- Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jai Prakash
- Engineered Therapeutics, Department of Advanced Organ bioengineering and Therapeutics, Technical Medical Centre, University of Twente, Enschede, The Netherlands.
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Kochumon S, Al-Sayyar A, Jacob T, Bahman F, Akhter N, Wilson A, Sindhu S, Hannun YA, Ahmad R, Al-Mulla F. TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis. Front Immunol 2024; 15:1430187. [PMID: 39351229 PMCID: PMC11439675 DOI: 10.3389/fimmu.2024.1430187] [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: 05/09/2024] [Accepted: 07/26/2024] [Indexed: 10/04/2024] Open
Abstract
Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-β and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-β/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.
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Affiliation(s)
- Shihab Kochumon
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Amnah Al-Sayyar
- Centre d’Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, Marseille, France
| | - Texy Jacob
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fatemah Bahman
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Nadeem Akhter
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Ajit Wilson
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Sardar Sindhu
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Yusuf A. Hannun
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, United States
| | - Rasheed Ahmad
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Translational Research, Dasman Diabetes Institute, Dasman, Kuwait
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6
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Zhao F, Wang L, Zhang Y, Tang S, Ji P, Xiang X, Pang X. MiR-494-3p regulates skin fibroblast activities by mediating fibromodulin production. J Cell Physiol 2024; 239:e31404. [PMID: 39129212 DOI: 10.1002/jcp.31404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 07/04/2024] [Accepted: 08/01/2024] [Indexed: 08/13/2024]
Abstract
Skin wound healing is a well-coordinated process in which various cells and factors participate, during which fibroblast exhibits a critical role by exerting its multiple activities, including proliferation, migration, invasion, and differentiation. Previous studies have identified that fibromodulin (FMOD) could enhance dermal wound healing by promoting skin fibroblast activities, but little is known about its upstream regulator. We occasionally found that FMOD expression was downregulated in skin fibroblast by transforming growth factor-β1 treatment. It was hypothesized that microRNAs (miRNA) in skin fibroblast could downregulate FMOD production and blocking them would increase FMOD expression, as well as promote skin wound healing. Here, by utilizing combined analysis of miRNA microarray from the Gene Expression Omnibus database and miRNA targets prediction, we successfully identified a miRNA, termed miR-494-3p, could regulate FMOD production in human skin fibroblast (BJ fibroblast). The functional analysis revealed that miR-494-3p mimics could inhibit BJ fibroblast migration and invasion but not proliferation and differentiation, while miR-494-3p inhibition markedly promotes migration, invasion, and differentiation of BJ fibroblast. Moreover, we established FMOD overexpression (OE) and knockout BJ fibroblast. We found that FMOD OE could rescue the inhibitory effects of miR-494-3p mimics on the migration and invasion of BJ fibroblast. In contrast, the miR-494-3p inhibitor transfection could not enhance migration, invasion, and differentiation of FMOD KO BJ fibroblast. Together, our results suggest that miR-494-3p may be a potential target for skin wound management via regulating FMOD production.
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Affiliation(s)
- Feng Zhao
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Linshu Wang
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Yuxin Zhang
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Siqi Tang
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Ji
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Xuerong Xiang
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoxiao Pang
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China
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Zhou H, Ye Z, Gao Z, Xi C, Yin J, Sun Y, Sun B. Construction of a pathological model of skin lesions in acute herpes zoster virus infection and its molecular mechanism. Mamm Genome 2024; 35:296-307. [PMID: 38600211 DOI: 10.1007/s00335-024-10039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/27/2024] [Indexed: 04/12/2024]
Abstract
Varicella-zoster virus (VZV), a common pathogen with humans as the sole host, causes primary infection and undergoes a latent period in sensory ganglia. The recurrence of VZV is often accompanied by severe neuralgia in skin tissue, which has a serious impact on the life of patients. During the acute infection of VZV, there are few related studies on the pathophysiological mechanism of skin tissue. In this study, transcriptome sequencing data from the acute response period within 2 days of VZV antigen stimulation of the skin were used to explore a model of the trajectory of skin tissue changes during VZV infection. It was found that early VZV antigen stimulation caused activation of mainly natural immune-related signaling pathways, while in the late phase activation of mainly active immune-related signaling pathways. JAK-STAT, NFκB, and TNFα signaling pathways are gradually activated with the progression of infection, while Hypoxia is progressively inhibited. In addition, we found that dendritic cell-mediated immune responses play a dominant role in the lesion damage caused by VZV antigen stimulation of the skin. This study provides a theoretical basis for the study of the molecular mechanisms of skin lesions during acute VZV infection.
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Affiliation(s)
- Hao Zhou
- Department of Anesthesia Surgery and Pain Management, Southeast University Zhongda Hospital, Nanjing, 210009, China
| | - Zheng Ye
- Institute of Computational Science and Technology, Guangzhou University, Nanjing, 510006, China
| | - Zhao Gao
- Department of Anesthesia Surgery and Pain Management, Southeast University Zhongda Hospital, Nanjing, 210009, China
| | - Chengxi Xi
- Department of Anesthesia Surgery and Pain Management, Southeast University Zhongda Hospital, Nanjing, 210009, China
| | - Jinxia Yin
- Department of Anesthesia Surgery and Pain Management, Southeast University Zhongda Hospital, Nanjing, 210009, China
| | - Yanjun Sun
- Department of Anesthesia Surgery and Pain Management, Southeast University Zhongda Hospital, Nanjing, 210009, China.
| | - Bo Sun
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, 210096, China.
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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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Lucena-Cacace A, Tian Y, Yoshida Y. Generation of 3D-Multicellular Human iPSC-Heart Organoids for the Noninvasive Assessment of Cardiac Fibrosis. Methods Mol Biol 2024; 2803:35-48. [PMID: 38676883 DOI: 10.1007/978-1-0716-3846-0_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2024]
Abstract
The lack of a precise noninvasive, clinical evaluation method for cardiac fibrosis hinders the development of successful treatments that can effectively work in physiological settings, where tissues and organs are interconnected and moderating drug responses. To address this challenge and advance personalized medicine, researchers have turned to human-induced pluripotent stem (iPS) cells, which can be differentiated to resemble the human heart in terms of structure, function and cellular composition. In this chapter, we present an assay protocol that uses these iPS cells to generate heart organoids for the in vitro evaluation of cardiac fibrosis. By establishing this biological platform, we pave the way for conducting phenotype evaluation and treatment screening in a multiscale approach, aiming to discover effective interventions for the treatment of cardiac fibrosis.
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Affiliation(s)
| | - Yu Tian
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshinori Yoshida
- Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
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10
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Mamat @ Yusof MN, Chew KT, Kampan NC, Shafiee MN. Expression of PD-1 and PD-L1 in Endometrial Cancer: Molecular and Clinical Significance. Int J Mol Sci 2023; 24:15233. [PMID: 37894913 PMCID: PMC10607163 DOI: 10.3390/ijms242015233] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
The landscape of diagnosing and treating endometrial cancer is undergoing a profound transformation due to the integration of molecular analysis and innovative therapeutic approaches. For several decades, the cornerstone treatments for endometrial cancer have included surgical resection, cytotoxic chemotherapy, hormonal therapy, and radiation therapy. However, in recent years, the concept of personalised medicine has gained momentum, reshaping the way clinicians approach cancer treatment. Tailoring treatments based on specific biomarkers has evolved into a standard practice in both initial and recurrent therapy protocols. This review aims to provide an in-depth exploration of the current state of molecular analysis and treatment strategies in the context of endometrial cancer, focusing on the immunological aspect of the PD-1/PD-L1 axis. Furthermore, it seeks to shed light on emerging and innovative approaches that hold promise for the future modulation of endometrial cancer treatments. In essence, as researchers delve into the complex molecular landscape of endometrial cancer and harness the understanding of the PD-1/PD-L1 axis, we are paving the way for more targeted, effective, and personalised therapies that have the potential to significantly improve the outcomes and quality of life for patients with this challenging disease.
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Affiliation(s)
| | | | | | - Mohamad Nasir Shafiee
- Gynaecologic-Oncology Unit, Department of Obstetrics and Gynaecology, Hospital Canselor Tuanku Muhriz, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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11
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Jeyamogan S, Leventhal JR, Mathew JM, Zhang ZJ. CD4 +CD25 +FOXP3 + regulatory T cells: a potential "armor" to shield "transplanted allografts" in the war against ischemia reperfusion injury. Front Immunol 2023; 14:1270300. [PMID: 37868962 PMCID: PMC10587564 DOI: 10.3389/fimmu.2023.1270300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/25/2023] [Indexed: 10/24/2023] Open
Abstract
Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4+CD25+FOXP3+ regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.
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Affiliation(s)
- Shareni Jeyamogan
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Joseph R. Leventhal
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - James M. Mathew
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Zheng Jenny Zhang
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Microsurgery and Pre-Clinical Research Core, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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12
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He X, Shao G, Du X, Hua R, Song H, Chen Y, Zhu X, Yang G. Molecular characterization and functional implications on mouse peripheral blood mononuclear cells of annexin proteins from Echinococcus granulosus sensu lato. Parasit Vectors 2023; 16:350. [PMID: 37803469 PMCID: PMC10559496 DOI: 10.1186/s13071-023-05967-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/09/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Cystic echinococcosis (CE) is a life-threatening zoonotic disease caused by the larval stage of Echinococcus granulosus sensu lato, which employs various strategies to evade the host immune system for survival. Recent advances have revealed the role of annexins as excretory/secretory products, providing new insights into the immune regulation by these proteins in the pathogenesis of CE. METHODS Echinococcus granulosus annexin B proteins EgANXB2, EgANXB18, EgANXB20, and EgANXB23 were cloned, expressed, and analyzed using bioinformatic tools. Membrane binding analysis was used to assess their bioactivity, while their immunoreactivity and tissue distribution characteristics were determined experimentally using western blotting and immunofluorescence staining, respectively. Furthermore, quantitative real-time reverse transcription PCR (qRT-PCR) was used to analyze the mRNA expression profiles of EgANXBs in different developmental stages of E. granulosus. Finally, immunofluorescence staining, cell counting kit 8 assays, flow cytometry, transwell migration assays, and qRT-PCR were used to evaluate the functional effects of rEgANXB18 and rEgANXB20 on mouse peripheral blood mononuclear cells (PBMCs). RESULTS In this study, we identified four EgANXBs with conserved protein structures and calcium-dependent phospholipid binding activities. rEgANXBs were recognized by serum from sheep infected with E. granulosus and distributed in the germinal layer of fertile cysts. Interestingly, transcription levels of the four EgANXBs were significantly higher in protoscoleces than in 28-day strobilated worms. Moreover, we demonstrated that rEgANXB18 and rEgANXB20 were secretory proteins that could bind to PBMCs and regulate their function. Specifically, rEgANXB18 inhibited cell proliferation and migration while promoting cell apoptosis, NO production, and cytokine profile shifting. In contrast, rEgANXB20 showed limited effects on apoptosis but inhibited NO production. CONCLUSIONS Our findings suggested that among the four identified EgANXBs, EgANXB2 and EgANXB23 might play a pivotal role for the development of protoscoleces, while EgANXB18 and EgANXB20, as secretory proteins, appeared to participate in the host-parasite interaction by regulating the function of immune cells.
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Affiliation(s)
- Xue He
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Guoqing Shao
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Xiaodi Du
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Ruiqi Hua
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Hongyu Song
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Yanxin Chen
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Xiaowei Zhu
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China
| | - Guangyou Yang
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan Province, People's Republic of China.
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Rahman T, Das A, Abir MH, Nafiz IH, Mahmud AR, Sarker MR, Emran TB, Hassan MM. Cytokines and their role as immunotherapeutics and vaccine Adjuvants: The emerging concepts. Cytokine 2023; 169:156268. [PMID: 37320965 DOI: 10.1016/j.cyto.2023.156268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
Cytokines are a protein family comprising interleukins, lymphokines, chemokines, monokines and interferons. They are significant constituents of the immune system, and they act in accordance with specific cytokine inhibiting compounds and receptors for the regulation of immune responses. Cytokine studies have resulted in the establishment of newer therapies which are being utilized for the treatment of several malignant diseases. The advancement of these therapies has occurred from two distinct strategies. The first strategy involves administrating the recombinant and purified cytokines, and the second strategy involves administrating the therapeutics which inhibits harmful effects of endogenous and overexpressed cytokines. Colony stimulating factors and interferons are two exemplary therapeutics of cytokines. An important effect of cytokine receptor antagonist is that they can serve as anti-inflammatory agents by altering the treatments of inflammation disorder, therefore inhibiting the effects of tumour necrosis factor. In this article, we have highlighted the research behind the establishment of cytokines as therapeutics and vaccine adjuvants, their role of immunotolerance, and their limitations.
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Affiliation(s)
- Tanjilur Rahman
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Ayan Das
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Mehedy Hasan Abir
- Faculty of Food Science and Technology, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh
| | - Iqbal Hossain Nafiz
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh
| | - Aar Rafi Mahmud
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
| | - Md Rifat Sarker
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chattogram 4381, Bangladesh; Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Mohammad Mahmudul Hassan
- Department of Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh; Queensland Alliance for One Health Sciences, School of Veterinary Science, The University of Queensland, Queensland 4343, Australia.
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14
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Jethalia M, Jani SP, Ceccarelli M, Mall R. Pancancer network analysis reveals key master regulators for cancer invasiveness. J Transl Med 2023; 21:558. [PMID: 37599366 PMCID: PMC10440887 DOI: 10.1186/s12967-023-04435-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 08/12/2023] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Tumor invasiveness reflects numerous biological changes, including tumorigenesis, progression, and metastasis. To decipher the role of transcriptional regulators (TR) involved in tumor invasiveness, we performed a systematic network-based pan-cancer assessment of master regulators of cancer invasiveness. MATERIALS AND METHODS We stratified patients in The Cancer Genome Atlas (TCGA) into invasiveness high (INV-H) and low (INV-L) groups using consensus clustering based on an established robust 24-gene signature to determine the prognostic association of invasiveness with overall survival (OS) across 32 different cancers. We devise a network-based protocol to identify TRs as master regulators (MRs) unique to INV-H and INV-L phenotypes. We validated the activity of MRs coherently associated with INV-H phenotype and worse OS across cancers in TCGA on a series of additional datasets in the Prediction of Clinical Outcomes from the Genomic Profiles (PRECOG) repository. RESULTS Based on the 24-gene signature, we defined the invasiveness score for each patient sample and stratified patients into INV-H and INV-L clusters. We observed that invasiveness was associated with worse survival outcomes in almost all cancers and had a significant association with OS in ten out of 32 cancers. Our network-based framework identified common invasiveness-associated MRs specific to INV-H and INV-L groups across the ten prognostic cancers, including COL1A1, which is also part of the 24-gene signature, thus acting as a positive control. Downstream pathway analysis of MRs specific to INV-H phenotype resulted in the identification of several enriched pathways, including Epithelial into Mesenchymal Transition, TGF-β signaling pathway, regulation of Toll-like receptors, cytokines, and inflammatory response, and selective expression of chemokine receptors during T-cell polarization. Most of these pathways have connotations of inflammatory immune response and feasibility for metastasis. CONCLUSION Our pan-cancer study provides a comprehensive master regulator analysis of tumor invasiveness and can suggest more precise therapeutic strategies by targeting the identified MRs and downstream enriched pathways for patients across multiple cancers.
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Affiliation(s)
- Mahesh Jethalia
- Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Siddhi P Jani
- Centre of Brain Research, Indian Institute of Sciences, Bangalore, Karnataka, India
- Institute of Science, Nirma University, Ahmedabad, India
| | - Michele Ceccarelli
- Department of Public Health Sciences, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Raghvendra Mall
- St. Jude Children's Hospital, Memphis, TN, USA.
- Biotechnology Research Center, Technology Innovation Institute, P.O. Box 9639, Abu Dhabi, United Arab Emirates.
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15
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Liu H, Wei Z, Zhang Y, Shi K, Li J. TGF-β based risk model to predict the prognosis and immune features in glioblastoma. Front Neurol 2023; 14:1188383. [PMID: 37456651 PMCID: PMC10343447 DOI: 10.3389/fneur.2023.1188383] [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: 03/17/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Background Transforming growth factor-β (TGF-β) is a multifunctional cytokine with an important role in tissue development and tumorigenesis. TGF-β can inhibit the function of many immune cells, prevent T cells from penetrating into the tumor center, so that the tumor cells escape from immune surveillance and lead to low sensitivity to immunotherapy. However, its potential roles in predicting clinical prognosis and tumor microenvironment (TME) immune features need to be deeply investigated in glioblastoma (GBM). Methods The TCGA-GBM dataset was obtained from the Cancer Genome Atlas, and the validation dataset was downloaded from Gene Expression Omnibus. Firstly, differentially expressed TGF-β genes (DEGs) were screened between GBM and normal samples. Then, univariate and multivariate Cox analyses were used to identify prognostic genes and develop the TGF-β risk model. Subsequently, the roles of TGF-β risk score in predicting clinical prognosis and immune characteristics were investigated. Results The TGF-β risk score signature with an independent prognostic value was successfully developed. The TGF-β risk score was positively correlated with the infiltration levels of tumor-infiltrating immune cells, and the activities of anticancer immunity steps. In addition, the TGF-β risk score was positively related to the expression of immune checkpoints. Besides, the high score indicated higher sensitivity to immune checkpoint inhibitors. Conclusions We first developed and validated a TGF-β risk signature that could predict the clinical prognosis and TME immune features for GBM. In addition, the TGF-β signature could guide a more personalized therapeutic approach for GBM.
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Yao Y, Li J, Qu K, Wang Y, Wang Z, Lu W, Yu Y, Wang L. Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-β2 inhibitor. Cancer Immunol Immunother 2022; 72:1103-1120. [PMID: 36326892 DOI: 10.1007/s00262-022-03315-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
Tumor immunotherapies have shown promising antitumor effects, especially immune checkpoint inhibitors (ICIs). However, only 12.46% of the patients benefit from the ICIs, the rest of them shows limited effects on ICIs or even accelerates the tumor progression due to the lack of the immune cell infiltration and activation in the tumor microenvironment (TME). In this study, we administrated a combination of Toll-like receptor 9 (TLR9) agonist CpG ODN and Transforming growth factor-β2 (TGF-β2) antisense oligodeoxynucleotide TIO3 to mice intraperitoneally once every other day for a total of four injections, and the first injection was 24 h after LLC cell inoculation. We found that the combination induced the formation of TME toward the enrichment and activation of CD8+ T cells and NK cells, accompanied with a marked decrease of TGF-β2. The combined therapy also effectively inhibited the tumor growth and prolonged the survival of the mice, even protected the tumor-free mice from the tumor re-challenge. Both of CpG ODN and TIO3 are indispensable, because replacing CpG ODN with TLR9 inhibitor CCT ODN showed no antitumor effect, CpG ODN or TIO3 alone did not lead to ideal antitumor results. This effect was possibly initiated by the activation of dendritic cells at the tumor site. This systemic antitumor immunotherapy with a combination of the two oligonucleotides (an immune stimulant and an immunosuppressive cytokine inhibitor) before the tumor formation may provide a novel strategy for clinical prevention of the postoperative tumor recurrence.
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Affiliation(s)
- Yunpeng Yao
- Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Jianhua Li
- Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Kuo Qu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Yangeng Wang
- Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Zhe Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Wenting Lu
- Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Yongli Yu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, People's Republic of China.
| | - Liying Wang
- Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People's Republic of China.
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GC S, Bellis SL, Hjelmeland AB. ST6Gal1: Oncogenic signaling pathways and targets. Front Mol Biosci 2022; 9:962908. [PMID: 36106023 PMCID: PMC9465715 DOI: 10.3389/fmolb.2022.962908] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
The Golgi-sialyltransferase ST6Gal1 (βgalactosidase α2,6 sialyltransferase 1), adds the negatively charged sugar, sialic acid, to the terminal galactose of N-glycosylated proteins. Upregulation of ST6Gal1 is observed in many malignancies, and a large body of research has determined that ST6Gal1-mediated α2,6 sialylation impacts cancer hallmarks. ST6Gal1 affects oncogenic behaviors including sustained proliferation, enhanced self-renewal, epithelial-to-mesenchymal transition, invasion, and chemoresistance. However, there are relatively few ST6GaL1 related signaling pathways that are well-established to mediate these biologies: greater delineation of specific targets and signaling mechanisms that are orchestrated by ST6Gal1 is needed. The aim of this review is to provide a summary of our current understanding of select oncogenic signaling pathways and targets affected by ST6Gal1.
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Affiliation(s)
| | | | - Anita B. Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
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18
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Li Z, Li Y, Shen L, Shen L, Li N. Molecular characterization, clinical relevance and immune feature of m7G regulator genes across 33 cancer types. Front Genet 2022; 13:981567. [PMID: 36092891 PMCID: PMC9453236 DOI: 10.3389/fgene.2022.981567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Over 170 RNA modifications have been identified after transcriptions, involving in regulation of RNA splicing, processing, translation and decay. Growing evidence has unmasked the crucial role of N6-methyladenosine (m6A) in cancer development and progression, while, as a relative newly found RNA modification, N7-methylguanosine (m7G) is also certified to participate in tumorigenesis via different catalytic machinery from that of m6A. However, system analysis on m7G RNA modification-related regulator genes is lack. In this study, we first investigated the genetic alteration of m7G related regulator genes in 33 cancers, and found mRNA expression levels of most regulator genes were positively correlated with copy number variation (CNV) and negatively correlated with methylation in most cancers. We built a m7G RNA modification model based on the enrichment of the regulator gene scores to evaluate the m7G modification levels in 33 cancers, and investigated the connections of m7G scores to clinical outcomes. Furthermore, we paid close attention to the role of m7G in immunology due to the widely used immune checkpoint blockade therapy. Our results showed the higher m7G scores related to immunosuppression of tumor cells. Further confirmation with phase 3 clinical data with application of anti-PDL1/PDL indicated the impact of m7G modification level on immunotherapy effect. Relevance of m7G regulator genes and drug sensitivity was also evaluated to provide a better treatment choice when treating cancers. In summary, our study uncovered the profile of m7G RNA modification through various cancers, and figured out the connection of m7G modification levels with therapeutical outcomes, providing potential better options of cancer treatment.
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Affiliation(s)
- Zhanzhan Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yanyan Li
- Department of Nursing, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Na Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Kanwore K, Kanwore K, Adzika GK, Abiola AA, Guo X, Kambey PA, Xia Y, Gao D. Cancer Metabolism: The Role of Immune Cells Epigenetic Alteration in Tumorigenesis, Progression, and Metastasis of Glioma. Front Immunol 2022; 13:831636. [PMID: 35392088 PMCID: PMC8980436 DOI: 10.3389/fimmu.2022.831636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/28/2022] [Indexed: 12/17/2022] Open
Abstract
Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family background of glioma constitute are risk factors of glioma initiation. Gliomas are categorized on a scale of four grades according to their growth rate. Grades one and two grow slowly, while grades three and four grow faster. Glioblastoma is a grade four gliomas and the deadliest due to its aggressive nature (accelerated proliferation, invasion, and migration). As such, multiple therapeutic approaches are required to improve treatment outcomes. Recently, studies have implicated the significant roles of immune cells in tumorigenesis and the progression of glioma. The energy demands of gliomas alter their microenvironment quality, thereby inducing heterogeneity and plasticity change of stromal and immune cells via the PI3K/AKT/mTOR pathway, which ultimately results in epigenetic modifications that facilitates tumor growth. PI3K is utilized by many intracellular signaling pathways ensuring the proper functioning of the cell. The activation of PI3K/AKT/mTOR regulates the plasma membrane activities, contributing to the phosphorylation reaction necessary for transcription factors activities and oncogenes hyperactivation. The pleiotropic nature of PI3K/AKT/mTOR makes its activity unpredictable during altered cellular functions. Modification of cancer cell microenvironment affects many cell types, including immune cells that are the frontline cells involved in inflammatory cascades caused by cancer cells via high cytokines synthesis. Typically, the evasion of immunosurveillance by gliomas and their resistance to treatment has been attributed to epigenetic reprogramming of immune cells in the tumor microenvironment, which results from cancer metabolism. Hence, it is speculative that impeding cancer metabolism and/or circumventing the epigenetic alteration of immune cell functions in the tumor microenvironment might enhance treatment outcomes. Herein, from an oncological and immunological perspective, this review discusses the underlying pathomechanism of cell-cell interactions enhancing glioma initiation and metabolism activation and tumor microenvironment changes that affect epigenetic modifications in immune cells. Finally, prospects for therapeutic intervention were highlighted.
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Affiliation(s)
- Kouminin Kanwore
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Konimpo Kanwore
- Faculty Mixed of Medicine and Pharmacy, Lomé-Togo, University of Lomé, Lomé, Togo
| | | | - Ayanlaja Abdulrahman Abiola
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Xiaoxiao Guo
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Piniel Alphayo Kambey
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Ying Xia
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Dianshuai Gao
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology, Xuzhou Medical University, Xuzhou, China.,Xuzhou Key Laboratory of Neurobiology, Department of Anatomy, Xuzhou Medical University, Xuzhou, China
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Mikuła-Pietrasik J, Rutecki S, Książek K. The functional multipotency of transforming growth factor β signaling at the intersection of senescence and cancer. Cell Mol Life Sci 2022; 79:196. [PMID: 35305149 PMCID: PMC11073081 DOI: 10.1007/s00018-022-04236-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/22/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022]
Abstract
The transforming growth factor β (TGF-β) family of cytokines comprises a group of proteins, their receptors, and effector molecules that, in a coordinated manner, modulate a plethora of physiological and pathophysiological processes. TGF-β1 is the best known and plausibly most active representative of this group. It acts as an immunosuppressant, contributes to extracellular matrix remodeling, and stimulates tissue fibrosis, differentiation, angiogenesis, and epithelial-mesenchymal transition. In recent years, this cytokine has been established as a vital regulator of organismal aging and cellular senescence. Finally, the role of TGF-β1 in cancer progression is no longer in question. Because this protein is involved in so many, often overlapping phenomena, the question arises whether it can be considered a molecular bridge linking some of these phenomena together and governing their reciprocal interactions. In this study, we reviewed the literature from the perspective of the role of various TGF-β family members as regulators of a complex mutual interplay between senescence and cancer. These aspects are then considered in a broader context of remaining TGF-β-related functions and coexisting processes. The main narrative axis in this work is centered around the interaction between the senescence of normal peritoneal cells and ovarian cancer cells. The discussion also includes examples of TGF-β activity at the interface of other normal and cancer cell types.
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Affiliation(s)
- Justyna Mikuła-Pietrasik
- Department of Pathophysiology of Ageing and Civilization Diseases, Długa ½ Str, Poznań University of Medical Sciences, 61-848, Poznań, Poland
| | - Szymon Rutecki
- Department of Pathophysiology of Ageing and Civilization Diseases, Długa ½ Str, Poznań University of Medical Sciences, 61-848, Poznań, Poland
| | - Krzysztof Książek
- Department of Pathophysiology of Ageing and Civilization Diseases, Długa ½ Str, Poznań University of Medical Sciences, 61-848, Poznań, Poland.
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21
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Mutlu L, Harold J, Tymon-Rosario J, Santin AD. Immune checkpoint inhibitors for recurrent endometrial cancer. Expert Rev Anticancer Ther 2022; 22:249-258. [PMID: 35176955 DOI: 10.1080/14737140.2022.2044311] [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: 11/04/2022]
Abstract
INTRODUCTION Endometrial cancer (EC) is the most common gynecologic malignancy. Outcomes for patients with advanced and/or recurrent disease have been modest with the use of chemotherapy. The approval of immune checkpoint inhibitors targeting PD-1 have recently revolutionized human cancer treatment. Recent trials with immune checkpoint inhibitors used alone or in combination with other agents, have demonstrated remarkable efficacy in the treatment of the all-comers EC patient population. AREAS COVERED In this article, we review major clinical trials on PD-1/PD-L1 inhibitors in advanced and recurrent EC and discuss the response rates to these agents in the context of their genomic background. EXPERT OPINION Immune checkpoint inhibitors have significantly changed our approach to the treatment of advanced/recurrent EC. Single agent anti-PD-1 regimens are highly effective in MMRd/MSI-H patients, but their clinical efficacy remains modest in MMR proficient/TMB low EC patients. Combination regimens that can decrease the tumor microenvironments immunosuppression and increase tumor immunogenicity represent a viable treatment option to broaden the activity of immune checkpoint inhibitors in advanced/recurrent EC patients. An increased understanding of the biomarkers of response and the molecular mechanisms of resistance to immune checkpoint inhibitors remains key for the next advancement of the field.
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Affiliation(s)
- Levent Mutlu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Smilow Cancer Hospital, Yale University, School of Medicine
| | - Justin Harold
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Smilow Cancer Hospital, Yale University, School of Medicine
| | - Joan Tymon-Rosario
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Smilow Cancer Hospital, Yale University, School of Medicine
| | - Alessandro D Santin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Smilow Cancer Hospital, Yale University, School of Medicine
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22
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Sorrentino C, D'Antonio L, Fieni C, Ciummo SL, Di Carlo E. Colorectal Cancer-Associated Immune Exhaustion Involves T and B Lymphocytes and Conventional NK Cells and Correlates With a Shorter Overall Survival. Front Immunol 2022; 12:778329. [PMID: 34975867 PMCID: PMC8716410 DOI: 10.3389/fimmu.2021.778329] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer worldwide, with a growing impact on public health and clinical management. Immunotherapy has shown promise in the treatment of advanced cancers, but needs to be improved for CRC, since only a limited fraction of patients is eligible for treatment, and most of them develop resistance due to progressive immune exhaustion. Here, we identify the transcriptional, molecular, and cellular traits of the immune exhaustion associated with CRC and determine their relationships with the patient's clinic-pathological profile. Bioinformatic analyses of RNA-sequencing data of 594 CRCs from TCGA PanCancer collection, revealed that, in the wide range of immune exhaustion genes, those coding for PD-L1, LAG3 and T-bet were associated (Cramér's V=0.3) with MSI/dMMR tumors and with a shorter overall survival (log-rank test: p=0.0004, p=0.0014 and p=0.0043, respectively), whereas high levels of expression of EOMES, TRAF1, PD-L1, FCRL4, BTLA and SIGLEC6 were associated with a shorter overall survival (log-rank test: p=0.0003, p=0.0188, p=0.0004, p=0.0303, p=0.0052 and p=0.0033, respectively), independently from the molecular subtype of CRC. Expression levels of PD-L1, PD-1, LAG3, EOMES, T-bet, and TIGIT were significantly correlated with each other and associated with genes coding for CD4+ and CD8+CD3+ T cell markers and NKp46+CD94+EOMES+T-bet+ cell markers, (OR >1.5, p<0.05), which identify a subset of group 1 innate lymphoid cells, namely conventional (c)NK cells. Expression of TRAF1 and BTLA co-occurred with both T cell markers, CD3γ, CD3δ, CD3ε, CD4, and B cell markers, CD19, CD20 and CD79a (OR >2, p<0.05). Expression of TGFβ1 was associated only with CD4 + and CD8+CD3ε+ T cell markers (odds ratio >2, p<0.05). Expression of PD-L2 and IDO1 was associated (OR >1.5, p<0.05) only with cNK cell markers, whereas expression of FCRL4, SIGLEC2 and SIGLEC6 was associated (OR >2.5; p<0.05) with CD19+CD20+CD79a+ B cell markers. Morphometric examination of immunostained CRC tissue sections, obtained from a validation cohort of 53 CRC patients, substantiated the biostatistical findings, showing that the highest percentage of immune exhaustion gene expressing cells were found in tumors from short-term survivors and that functional exhaustion is not confined to T lymphocytes, but also involves B cells, and cNK cells. This concept was strengthened by CYBERSORTx analysis, which revealed the expression of additional immune exhaustion genes, in particular FOXP1, SIRT1, BATF, NR4A1 and TOX, by subpopulations of T, B and NK cells. This study provides novel insight into the immune exhaustion landscape of CRC and emphasizes the need for a customized multi-targeted therapeutic approach to overcome resistance to current immunotherapy.
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Affiliation(s)
- Carlo Sorrentino
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University" of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Luigi D'Antonio
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University" of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Cristiano Fieni
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University" of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Stefania Livia Ciummo
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University" of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Emma Di Carlo
- Department of Medicine and Sciences of Aging, "G. d'Annunzio" University" of Chieti-Pescara, Chieti, Italy.,Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
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23
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Soltani M, Rezaei M, Fekrvand S, Ganjalikhani-Hakemi M, Abolhassani H, Yazdani R. Role of rare immune cells in common variable immunodeficiency. Pediatr Allergy Immunol 2022; 33:e13725. [PMID: 34937129 DOI: 10.1111/pai.13725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/10/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
Common variable immunodeficiency disorder (CVID) is a heterogeneous disorder and the most common symptomatic antibody deficiency disease characterized with hypogammaglobulinemia and a broad range of clinical manifestations. Multiple genetic, epigenetic, and immunological defects are involved in the pathogenesis of CVID. These immunological defects include abnormalities in the number and/or function of B lymphocytes, T lymphocytes, and other rare immune cells. Although some immune cells have a relatively lower proportion among total immune subsets in the human body, they could have important roles in the pathogenesis of immunological disorders like CVID. To the best of our knowledge, this is the first review that described the role of rare immune cells in the pathogenesis and clinical presentations of CVID.
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Affiliation(s)
- Mojdeh Soltani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahnaz Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saba Fekrvand
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mazdak Ganjalikhani-Hakemi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Reza Yazdani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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24
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Brammer J, Choi M, Baliban SM, Kambouris AR, Fiskum G, Chao W, Lopez K, Miller C, Al-Abed Y, Vogel SN, Simon R, Cross AS. A Nonlethal Murine Flame Burn Model Leads to a Transient Reduction in Host Defenses and Enhanced Susceptibility to Lethal Pseudomonas aeruginosa Infection. Infect Immun 2021; 89:e0009121. [PMID: 34152806 PMCID: PMC8445176 DOI: 10.1128/iai.00091-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 06/01/2021] [Indexed: 12/03/2022] Open
Abstract
Of the 486,000 burn injuries that required medical treatment in the United States in 2016, 40,000 people were hospitalized, with >3,000 fatalities. After burn injury, humans are at increased risk of sepsis and mortality from infections caused by Pseudomonas aeruginosa, an opportunistic pathogen. We hypothesize that systemic events were initiated from the burn that increased the host's susceptibility to P. aeruginosa. A nonlethal 10% total body surface area (TBSA), full-thickness flame burn was performed in CD-1 mice without and with subsequent P. aeruginosa (strain M2) infection. The 50% lethal dose for subcutaneous infection with P. aeruginosa M2 at the burn site immediately after the burn decreased by 6 log, with mortality occurring between 18 and 26 h, compared with P. aeruginosa-infected mice without burn injury. Bacteria in distal organs were detected by 18 h, concurrent with the onset of clinical symptoms. Serum proinflammatory cytokines (interleukin-6 [IL-6], IL-1β, gamma interferon, and tumor necrosis factor alpha) and the anti-inflammatory cytokine IL-10 were first detected at 12 h postburn with infection and continued to increase until death. Directly after burn alone, serum levels of HMGB1, a danger-associated molecular pattern and TLR4 agonist, transiently increased to 50 ng/ml before returning to 20 ng/ml. Burn with P. aeruginosa infection increased serum HMGB1 concentrations >10-fold (250 ng/ml) at the time of death. This HMGB1-rich serum stimulated TLR4-mediated NF-κB activation in a TLR4 reporter cell line. Treatment of infected burned mice with P5779, a peptide inhibitor of HMGB1, increased the mean survival from 23 to 42 h (P < 0.0001). We conclude that the high level of serum HMGB1, which preceded the increase in proinflammatory cytokines, is associated with postburn mortality.
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Affiliation(s)
- Jerod Brammer
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Myeongjin Choi
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Scott M. Baliban
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Adrienne R. Kambouris
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Gary Fiskum
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Kerri Lopez
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Catriona Miller
- Enroute Care Division, Department of Aeromedical Research, USAF School of Aerospace Medicine, Wright Patterson AFB, Dayton, Ohio, USA
| | - Yousef Al-Abed
- Department of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| | - Stefanie N. Vogel
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Raphael Simon
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Alan S. Cross
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
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25
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Hopkins T, Wright KT, Kuiper NJ, Roberts S, Jermin P, Gallacher P, Kuiper JH. An In Vitro System to Study the Effect of Subchondral Bone Health on Articular Cartilage Repair in Humans. Cells 2021; 10:1903. [PMID: 34440671 PMCID: PMC8392168 DOI: 10.3390/cells10081903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/19/2022] Open
Abstract
Chondrocyte-based cartilage repair strategies, such as articular chondrocyte implantation, are widely used, but few studies addressed the communication between native subchondral bone cells and the transplanted chondrocytes. An indirect co-culture model was developed, representing a chondrocyte/scaffold-construct repair of a cartilage defect adjoining bone, where the bone could have varying degrees of degeneration. Human BM-MSCs were isolated from two areas of subchondral bone in each of five osteochondral tissue specimens from five patients undergoing knee arthroplasty. These two areas underlaid the macroscopically and histologically best and worst cartilage, representing early and late-stage OA, respectively. BM-MSCs were co-cultured with normal chondrocytes suspended in agarose, with the two cell types separated by a porous membrane. After 0, 7, 14 and 21 days, chondrocyte-agarose scaffolds were assessed by gene expression and biochemical analyses, and the abundance of selected proteins in conditioned media was assessed by ELISA. Co-culture with late-OA BM-MSCs resulted in a reduction in GAG deposition and a decreased expression of genes encoding matrix-specific proteins (COL2A1 and ACAN), compared to culturing with early OA BM-MSCs. The concentration of TGF-β1 was significantly higher in the early OA conditioned media. The results of this study have clinical implications for cartilage repair, suggesting that the health of the subchondral bone may influence the outcomes of chondrocyte-based repair strategies.
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Affiliation(s)
- Timothy Hopkins
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
| | - Karina T. Wright
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
| | - Nicola J. Kuiper
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
| | - Sally Roberts
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
| | - Paul Jermin
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
| | - Peter Gallacher
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
| | - Jan Herman Kuiper
- School of Pharmacy and Bioengineering, Keele University, Staffordshire ST5 5BG, UK; (K.T.W.); (N.J.K.); (S.R.); (P.J.); (P.G.); (J.H.K.)
- Robert Jones and Agnes Hunt Orthopaedic Hospital, Shropshire SY10 7AG, UK
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26
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Parajuli B, Saito H, Shinozaki Y, Shigetomi E, Miwa H, Yoneda S, Tanimura M, Omachi S, Asaki T, Takahashi K, Fujita M, Nakashima K, Koizumi S. Transnasal transplantation of human induced pluripotent stem cell-derived microglia to the brain of immunocompetent mice. Glia 2021; 69:2332-2348. [PMID: 34309082 DOI: 10.1002/glia.23985] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/15/2021] [Accepted: 02/19/2021] [Indexed: 01/26/2023]
Abstract
Microglia are the resident immune cells of the brain, and play essential roles in neuronal development, homeostatic function, and neurodegenerative disease. Human microglia are relatively different from mouse microglia. However, most research on human microglia is performed in vitro, which does not accurately represent microglia characteristics under in vivo conditions. To elucidate the in vivo characteristics of human microglia, methods have been developed to generate and transplant induced pluripotent or embryonic stem cell-derived human microglia into neonatal or adult mouse brains. However, its widespread use remains limited by the technical difficulties of generating human microglia, as well as the need to use immune-deficient mice and conduct invasive surgeries. To address these issues, we developed a simplified method to generate induced pluripotent stem cell-derived human microglia and transplant them into the brain via a transnasal route in immunocompetent mice, in combination with a colony stimulating factor 1 receptor antagonist. We found that human microglia were able to migrate through the cribriform plate to different regions of the brain, proliferate, and become the dominant microglia in a region-specific manner by occupying the vacant niche when exogenous human cytokine is administered, for at least 60 days.
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Affiliation(s)
- Bijay Parajuli
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Hiroki Saito
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Youichi Shinozaki
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Eiji Shigetomi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Hiroto Miwa
- Laboratory for Innovative Therapy Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Sosuke Yoneda
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Miki Tanimura
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Shigeki Omachi
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Toshiyuki Asaki
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Koji Takahashi
- Laboratory for Innovative Therapy Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Masahide Fujita
- Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Osaka, Japan
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Schuichi Koizumi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.,GLIA Center, University of Yamanashi, Yamanashi, Japan
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27
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Wang E, Chen H, Sun B, Wang H, Qu H, Liu Y, Sun X, Qu J, Fang Z, Tian L, Zeng Y, Huang S, Hakonarson H, Liu Z. Serum levels of the IgA isotype switch factor TGF-β1 are elevated in patients with COVID-19. FEBS Lett 2021; 595:1819-1824. [PMID: 33961290 PMCID: PMC8209884 DOI: 10.1002/1873-3468.14104] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/25/2021] [Accepted: 04/30/2021] [Indexed: 01/27/2023]
Abstract
We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID-19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF-β1 in COVID-19 patients. We observed, in a total of 153 COVID-19 patients, that the serum levels of TGF-β1 were increased significantly at the early and middle stages of COVID-19, and correlated with the levels of SARS-CoV-2-specific IgA, as well as with the APACHE II score in patients with severe disease. In view of the genetic association of the TGF-β1 activator THBS3 with severe COVID-19 identified by the COVID-19 Host Genetics Initiative, this study suggests TGF-β1 may play a key role in COVID-19.
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Affiliation(s)
- Er‐yi Wang
- Shenzhen Key Laboratory of Allergy & ImmunologyState Key Laboratory of Respiratory Disease for Allergy at Shenzhen UniversityShenzhen University School of MedicineChina
- Department of Respirology & AllergyThird Affiliated Hospital of Shenzhen UniversityChina
| | - Hao Chen
- Department of Allergy, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory DiseaseFirst Affiliated Hospital of Guangzhou Medical UniversityChina
| | - Bao‐qing Sun
- State Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthFirst Affiliated Hospital of Guangzhou Medical UniversityChina
| | - Hui Wang
- Department of Medical LaboratoryThe Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hui‐Qi Qu
- Center for Applied GenomicsThe Children’s Hospital of PhiladelphiaPAUSA
| | - Yichuan Liu
- Center for Applied GenomicsThe Children’s Hospital of PhiladelphiaPAUSA
| | - Xi‐zhuo Sun
- Department of Respirology & AllergyThird Affiliated Hospital of Shenzhen UniversityChina
| | - Jingchun Qu
- Center for Applied GenomicsThe Children’s Hospital of PhiladelphiaPAUSA
| | - Zhang‐fu Fang
- Shenzhen Key Laboratory of Allergy & ImmunologyState Key Laboratory of Respiratory Disease for Allergy at Shenzhen UniversityShenzhen University School of MedicineChina
- Department of Respirology & AllergyThird Affiliated Hospital of Shenzhen UniversityChina
| | - Lifeng Tian
- Center for Applied GenomicsThe Children’s Hospital of PhiladelphiaPAUSA
| | - Yi‐feng Zeng
- State Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthFirst Affiliated Hospital of Guangzhou Medical UniversityChina
| | - Shau‐Ku Huang
- Shenzhen Key Laboratory of Allergy & ImmunologyState Key Laboratory of Respiratory Disease for Allergy at Shenzhen UniversityShenzhen University School of MedicineChina
- National Health Research InstitutesMiaoliTaiwan
| | - Hakon Hakonarson
- Center for Applied GenomicsThe Children’s Hospital of PhiladelphiaPAUSA
- Division of Human Genetics & Division of Pulmonary MedicineChildren’s Hospital of PhiladelphiaPAUSA
| | - Zhi‐gang Liu
- Shenzhen Key Laboratory of Allergy & ImmunologyState Key Laboratory of Respiratory Disease for Allergy at Shenzhen UniversityShenzhen University School of MedicineChina
- Department of Respirology & AllergyThird Affiliated Hospital of Shenzhen UniversityChina
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28
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Cao W, Ma X, Fischer JV, Sun C, Kong B, Zhang Q. Immunotherapy in endometrial cancer: rationale, practice and perspectives. Biomark Res 2021; 9:49. [PMID: 34134781 PMCID: PMC8207707 DOI: 10.1186/s40364-021-00301-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.
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Affiliation(s)
- Wenyu Cao
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Xinyue Ma
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Jean Victoria Fischer
- Department of Pathology, Northwestern Medicine, Gynecologic Pathology Fellow, Chicago, Illinois, USA
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China.,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China
| | - Qing Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Ji'nan, Shandong, 250012, P.R. China. .,Gynecology Oncology Key Laboratory, Qilu Hospital, Shandong University, Ji'nan, Shandong, 250012, P.R. China.
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29
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Kudela E, Liskova A, Samec M, Koklesova L, Holubekova V, Rokos T, Kozubik E, Pribulova T, Zhai K, Busselberg D, Kubatka P, Biringer K. The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer. EPMA J 2021; 12:199-220. [PMID: 34194585 PMCID: PMC8192654 DOI: 10.1007/s13167-021-00244-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/04/2021] [Indexed: 12/20/2022]
Abstract
HPVs representing the most common sexually transmitted disease are a group of carcinogenic viruses with different oncogenic potential. The immune system and the vaginal microbiome represent the modifiable and important risk factors in HPV-induced carcinogenesis. HPV infection significantly increases vaginal microbiome diversity, leading to gradual increases in the abundance of anaerobic bacteria and consequently the severity of cervical dysplasia. Delineation of the exact composition of the vaginal microbiome and immune environment before HPV acquisition, during persistent/progressive infections and after clearance, provides insights into the complex mechanisms of cervical carcinogenesis. It gives hints regarding the prediction of malignant potential. Relative high HPV prevalence in the general population is a challenge for modern and personalized diagnostics and therapeutic guidelines. Identifying the dominant microbial biomarkers of high-grade and low-grade dysplasia could help us to triage the patients with marked chances of lesion regression or progression. Any unnecessary surgical treatment of cervical dysplasia could negatively affect obstetrical outcomes and sexual life. Therefore, understanding the effect and role of microbiome-based therapies is a breaking point in the conservative management of HPV-associated precanceroses. The detailed evaluation of HPV capabilities to evade immune mechanisms from various biofluids (vaginal swabs, cervicovaginal lavage/secretions, or blood) could promote the identification of new immunological targets for novel individualized diagnostics and therapy. Qualitative and quantitative assessment of local immune and microbial environment and associated risk factors constitutes the critical background for preventive, predictive, and personalized medicine that is essential for improving state-of-the-art medical care in patients with cervical precanceroses and cervical cancer. The review article focuses on the influence and potential diagnostic and therapeutic applications of the local innate immune system and the microbial markers in HPV-related cancers in the context of 3P medicine.
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Affiliation(s)
- Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Veronika Holubekova
- Jessenius Faculty of Medicine, Biomedical Centre Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Tomas Rokos
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Erik Kozubik
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Terezia Pribulova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Dietrich Busselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
- European Association for Predictive, Preventive and Personalised Medicine, EPMA, 1160 Brussels, Belgium
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 036 01 Martin, Slovakia
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30
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Gu M, Gao Y, Chang P. KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas. Cancers (Basel) 2021; 13:cancers13102429. [PMID: 34069772 PMCID: PMC8157241 DOI: 10.3390/cancers13102429] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/22/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The vast majority of patients with pancreatic ductal adenocarcinomas harbor KRAS mutations in their tumors. Functionally, mutated KRAS is not only dedicated to tumor cell proliferation, survival and invasiveness, but also causing the immunosuppression in this cancer. In this situation, current data indicating the therapeutic effects of immune checkpoint inhibitors on pancreatic ductal adenocarcinomas are still not satisfying. In order to reflect the present bottleneck of immune checkpoint inhibitors in managing this cancer, we mainly provide information associated with the mechanism by which KRAS mutations establish the immunosuppressive milieus in pancreatic ductal adenocarcinomas. Together with other advances in this field, future directions to overcome the KRAS mutation-induced immunosuppression in pancreatic ductal adenocarcinomas are raised as well. Meanwhile, lung adenocarcinomas and colorectal adenocarcinomas are enumerated to compare with pancreatic ductal adenocarcinomas, aiming to indicate the specificity of KRAS mutations in dictating tumoral immune milieus among these cancers. Abstract Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.
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Affiliation(s)
- Meichen Gu
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China;
| | - Yanli Gao
- Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun 130021, China;
| | - Pengyu Chang
- Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, China;
- Correspondence: ; Tel.: +86-88783840; Fax: +86-431-88783840
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Gu YY, Dou JY, Huang XR, Liu XS, Lan HY. Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis. Front Physiol 2021; 12:684236. [PMID: 34054586 PMCID: PMC8155637 DOI: 10.3389/fphys.2021.684236] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 12/17/2022] Open
Abstract
Renal fibrosis is one of the most characterized pathological features in chronic kidney disease (CKD). Progressive fibrosis eventually leads to renal failure, leaving dialysis or allograft transplantation the only clinical option for CKD patients. Transforming growth factor-β (TGF-β) is the key mediator in renal fibrosis and is an essential regulator for renal inflammation. Therefore, the general blockade of the pro-fibrotic TGF-β may reduce fibrosis but may risk promoting renal inflammation and other side effects due to the diverse role of TGF-β in kidney diseases. Long non-coding RNAs (lncRNAs) are RNA transcripts with more than 200 nucleotides and have been regarded as promising therapeutic targets for many diseases. This review focuses on the importance of TGF-β and lncRNAs in renal inflammation, fibrogenesis, and the potential applications of TGF-β and lncRNAs as the therapeutic targets and biomarkers in renal fibrosis and CKD are highlighted.
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Affiliation(s)
- Yue-Yu Gu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing-Yun Dou
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Nephrology, Weihai Hospital of Traditional Chinese Medicine, Weihai, China
| | - Xiao-Ru Huang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xu-Sheng Liu
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, The Chinese University of Hong Kong, Hong Kong, China
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Mall R, Saad M, Roelands J, Rinchai D, Kunji K, Almeer H, Hendrickx W, M Marincola F, Ceccarelli M, Bedognetti D. Network-based identification of key master regulators associated with an immune-silent cancer phenotype. Brief Bioinform 2021; 22:6274817. [PMID: 33979427 PMCID: PMC8574720 DOI: 10.1093/bib/bbab168] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/24/2021] [Accepted: 04/09/2021] [Indexed: 12/15/2022] Open
Abstract
A cancer immune phenotype characterized by an active T-helper 1 (Th1)/cytotoxic response is associated with responsiveness to immunotherapy and favorable prognosis across different tumors. However, in some cancers, such an intratumoral immune activation does not confer protection from progression or relapse. Defining mechanisms associated with immune evasion is imperative to refine stratification algorithms, to guide treatment decisions and to identify candidates for immune-targeted therapy. Molecular alterations governing mechanisms for immune exclusion are still largely unknown. The availability of large genomic datasets offers an opportunity to ascertain key determinants of differential intratumoral immune response. We follow a network-based protocol to identify transcription regulators (TRs) associated with poor immunologic antitumor activity. We use a consensus of four different pipelines consisting of two state-of-the-art gene regulatory network inference techniques, regularized gradient boosting machines and ARACNE to determine TR regulons, and three separate enrichment techniques, including fast gene set enrichment analysis, gene set variation analysis and virtual inference of protein activity by enriched regulon analysis to identify the most important TRs affecting immunologic antitumor activity. These TRs, referred to as master regulators (MRs), are unique to immune-silent and immune-active tumors, respectively. We validated the MRs coherently associated with the immune-silent phenotype across cancers in The Cancer Genome Atlas and a series of additional datasets in the Prediction of Clinical Outcomes from Genomic Profiles repository. A downstream analysis of MRs specific to the immune-silent phenotype resulted in the identification of several enriched candidate pathways, including NOTCH1, TGF-$\beta $, Interleukin-1 and TNF-$\alpha $ signaling pathways. TGFB1I1 emerged as one of the main negative immune modulators preventing the favorable effects of a Th1/cytotoxic response.
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Affiliation(s)
- Raghvendra Mall
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Mohamad Saad
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Jessica Roelands
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar
| | - Darawan Rinchai
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar
| | - Khalid Kunji
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Hossam Almeer
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Wouter Hendrickx
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar
| | | | - Michele Ceccarelli
- Department of Electrical Engineering and Information Technology (DIETI), University of Naples "Federico II", Via Claudio 21, 80215 Naples, Italy.,Biogem, Istituto di Biologia e Genetica Molecolare, Via Camporeale, Ariano Irpino (AV)
| | - Davide Bedognetti
- Cancer Research Department, Research Branch, Sidra Medicince, Doha, Qatar.,Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy.,College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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Sakai R, Ito M, Komai K, Iizuka-Koga M, Matsuo K, Nakayama T, Yoshie O, Amano K, Nishimasu H, Nureki O, Kubo M, Yoshimura A. Kidney GATA3 + regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury. Cell Mol Immunol 2021; 18:1249-1261. [PMID: 32917984 PMCID: PMC8093306 DOI: 10.1038/s41423-020-00547-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/24/2020] [Indexed: 12/17/2022] Open
Abstract
FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30-35% of CD4+ T cells) during the late stage (days 21-90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.
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Affiliation(s)
- Ryota Sakai
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
- Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, 350-8550, Japan.
| | - Minako Ito
- Medical Institute of Bioregulation Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kyoko Komai
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Mana Iizuka-Koga
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazuhiko Matsuo
- Division of Chemotherapy, Kindai University Faculty of Pharmacy, Higashi-Osaka, 577-8502, Japan
| | - Takashi Nakayama
- Division of Chemotherapy, Kindai University Faculty of Pharmacy, Higashi-Osaka, 577-8502, Japan
| | - Osamu Yoshie
- The Health and Kampo Institute, Sendai, Miyagi, 981-3205, Japan
| | - Koichi Amano
- Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, 350-8550, Japan
| | - Hiroshi Nishimasu
- Department of Biological Science, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Osamu Nureki
- Department of Biological Science, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Masato Kubo
- Center for Animal Disease Models, Research Institute for Biomedical Science, Tokyo University of Science, 2669 Yamazaki, Noda-shi, Chiba, 278-0022, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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Semenova E, Grudniak MP, Machaj EK, Bocian K, Chroscinska-Krawczyk M, Trochonowicz M, Stepaniec IM, Murzyn M, Zagorska KE, Boruczkowski D, Kolanowski TJ, Oldak T, Rozwadowska N. Mesenchymal Stromal Cells from Different Parts of Umbilical Cord: Approach to Comparison & Characteristics. Stem Cell Rev Rep 2021; 17:1780-1795. [PMID: 33860454 PMCID: PMC8553697 DOI: 10.1007/s12015-021-10157-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) are a unique population of cells that play an important role in the regeneration potential of the body. MSCs exhibit a characteristic phenotype and are capable of modulating the immune response. MSCs can be isolated from various tissues such as: bone marrow, adipose tissue, placenta, umbilical cord and others. The umbilical cord as a source of MSCs, has strong advantages, such as no-risk procedure of tissue retrieval after birth and easiness of the MSCs isolation. As the umbilical cord (UC) is a complex organ and we decided to evaluate, whether the cells derived from different regions of umbilical cord show similar or distinct properties. In this study we characterized and compared MSCs from three regions of the umbilical cord: Wharton's Jelly (WJ), the perivascular space (PRV) and the umbilical membrane (UCM). The analysis was carried out in terms of morphology, phenotype, immunomodulation potential and secretome. Based on the obtained results, we were able to conclude, that MSCs derived from distinct UC regions differ in their properties. According to our result WJ-MSCs have high and stabile proliferation potential and phenotype, when compare with other MSCs and can be treated as a preferable source of cells for medical application.
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Affiliation(s)
- Ekaterina Semenova
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Mariusz P Grudniak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Eugeniusz K Machaj
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Katarzyna Bocian
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Faculty of Biology, Department of Immunology, University of Warsaw, Warsaw, Poland
| | | | - Marzena Trochonowicz
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Igor M Stepaniec
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Magdalena Murzyn
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Karolina E Zagorska
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Dariusz Boruczkowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Tomasz J Kolanowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Tomasz Oldak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.
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Lan HR, Du WL, Liu Y, Mao CS, Jin KT, Yang X. Role of immune regulatory cells in breast cancer: Foe or friend? Int Immunopharmacol 2021; 96:107627. [PMID: 33862552 DOI: 10.1016/j.intimp.2021.107627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022]
Abstract
Breast cancer (BC) is the most common cancer among women between the ages of 20 and 50, affecting more than 2.1 million people and causing the annual death of more than 627,000 women worldwide. Based on the available knowledge, the immune system and its components are involved in the pathogenesis of several malignancies, including BC. Cancer immunobiology suggests that immune cells can play a dual role and induce anti-tumor or immunosuppressive responses, depending on the tumor microenvironment (TME) signals. The most important effector immune cells with anti-tumor properties are natural killer (NK) cells, B, and T lymphocytes. On the other hand, immune and non-immune cells with regulatory/inhibitory phenotype, including regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic dendritic cells (tDCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and regulatory natural killer cells (NKregs), can promote the growth and development of tumor cells by inhibiting anti-tumor responses, inducing angiogenesis and metastasis, as well as the expression of inhibitory molecules and suppressor mediators of the immune system. However, due to the complexity of the interaction and the modification in the immune cells' phenotype and the networking of the immune responses, the exact mechanism of action of the immunosuppressive and regulatory cells is not yet fully understood. This review article reviews the immune responses involved in BC as well as the role of regulatory and inhibitory cells in the pathogenesis of the disease. Finally, therapeutic approaches based on inhibition of immunosuppressive responses derived from regulatory cells are discussed.
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Affiliation(s)
- Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Wen-Lin Du
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China; Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China
| | - Yuyao Liu
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Chun-Sen Mao
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Xue Yang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China.
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Zhang M, Xu M, Wang K, Li L, Zhao J. Effect of Inhibition of the JAK2/STAT3 Signaling Pathway on the Th17/IL-17 Axis in Acute Cellular Rejection After Heart Transplantation in Mice. J Cardiovasc Pharmacol 2021; 77:614-620. [PMID: 33951698 PMCID: PMC8096315 DOI: 10.1097/fjc.0000000000001007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 02/11/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Acute immune rejection is one of the most serious complications of heart transplantation, and its mechanism has always been a hot spot. Th17 cells and cytokine interleukin-17 (IL-17) have been proved to be involved in acute immune rejection, and the signaling pathway mechanism has attracted our interest. It has been confirmed that the Janus kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the differentiation of CD4+ T cells, so we focus on whether the JAK2/STAT3 signaling pathway is involved in the occurrence of acute immune rejection by regulating the Th17/IL-17 axis. In this study, we used Bagg's Albino c mice and C57BL/6 mice to construct heterotopic heart transplantation models, which were divided into the acute rejection group and AG490-treated group (n = 5), and donor tissue and serum were collected in 3 experimental days from the recipient mice for H&E staining analysis of paraffin sections and ELISA, Western blot, flow cytometry, and real time-polymerase chain reaction. The results showed that the acute rejection rating of the heart decreased, and the expression of related factors decreased significantly after using the inhibitor AG490, suggesting that the JAK2/STAT3 signaling pathway regulates expression of the Th17/IL-17 axis in cardiac allograft rejection.
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Affiliation(s)
- Ming Zhang
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Ming Xu
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Kaijie Wang
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Long Li
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Jinping Zhao
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
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Donini C, Rotolo R, Proment A, Aglietta M, Sangiolo D, Leuci V. Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective. Cells 2021; 10:cells10030543. [PMID: 33806296 PMCID: PMC8001974 DOI: 10.3390/cells10030543] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 02/08/2023] Open
Abstract
The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes.
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Affiliation(s)
- Chiara Donini
- Department of Oncology, University of Turin, 10124 Turin, Italy; (C.D.); (A.P.); (M.A.)
- Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; (R.R.); (V.L.)
| | - Ramona Rotolo
- Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; (R.R.); (V.L.)
| | - Alessia Proment
- Department of Oncology, University of Turin, 10124 Turin, Italy; (C.D.); (A.P.); (M.A.)
| | - Massimo Aglietta
- Department of Oncology, University of Turin, 10124 Turin, Italy; (C.D.); (A.P.); (M.A.)
- Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; (R.R.); (V.L.)
| | - Dario Sangiolo
- Department of Oncology, University of Turin, 10124 Turin, Italy; (C.D.); (A.P.); (M.A.)
- Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; (R.R.); (V.L.)
- Correspondence: ; Tel.: +39-011-993-3503; Fax: +39-011-993-3522
| | - Valeria Leuci
- Candiolo Cancer Institute, FPO–IRCCS, Str. Prov. 142, km 3,95, 10060 Candiolo (TO), Italy; (R.R.); (V.L.)
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Gebremeskel S, Nelson A, Walker B, Oliphant T, Lobert L, Mahoney D, Johnston B. Natural killer T cell immunotherapy combined with oncolytic vesicular stomatitis virus or reovirus treatments differentially increases survival in mouse models of ovarian and breast cancer metastasis. J Immunother Cancer 2021; 9:e002096. [PMID: 33722907 PMCID: PMC7970295 DOI: 10.1136/jitc-2020-002096] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Oncolytic viruses reduce tumor burden in animal models and have generated promising results in clinical trials. However, it is likely that oncolytic viruses will be more effective when used in combination with other therapies. Current therapeutic approaches, including chemotherapeutics, come with dose-limiting toxicities. Another option is to combine oncolytic viruses with immunotherapeutic approaches. METHODS Using experimental models of metastatic 4T1 breast cancer and ID8 ovarian peritoneal carcinomatosis, we examined natural killer T (NKT) cell-based immunotherapy in combination with recombinant oncolytic vesicular stomatitis virus (VSV) or reovirus. 4T1 mammary carcinoma cells or ID8 ovarian cancer cells were injected into syngeneic mice. Tumor-bearing mice were treated with VSV or reovirus followed by activation of NKT cells via the intravenous administration of autologous dendritic cells loaded with the glycolipid antigen α-galactosylceramide. The effects of VSV and reovirus on immunogenic cell death (ICD), cell viability and immunogenicity were tested in vitro. RESULTS VSV or reovirus treatments followed by NKT cell activation mediated greater survival in the ID8 model than individual therapies. The regimen was less effective when the treatment order was reversed, delivering virus treatments after NKT cell activation. In the 4T1 model, VSV combined with NKT cell activation increased overall survival and decreased metastatic burden better than individual treatments. In contrast, reovirus was not effective on its own or in combination with NKT cell activation. In vitro, VSV killed a panel of tumor lines better than reovirus. VSV infection also elicited greater increases in mRNA transcripts for proinflammatory cytokines, chemokines, and antigen presentation machinery compared with reovirus. Oncolytic VSV also induced the key hallmarks of ICD (calreticulin mobilization, plus release of ATP and HMGB1), while reovirus only mobilized calreticulin. CONCLUSION Taken together, these results demonstrate that oncolytic VSV and NKT cell immunotherapy can be effectively combined to decrease tumor burden in models of metastatic breast and ovarian cancers. Oncolytic VSV and reovirus induced differential responses in our models which may relate to differences in virus activity or tumor susceptibility.
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Affiliation(s)
- Simon Gebremeskel
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Adam Nelson
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Brynn Walker
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Tora Oliphant
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Lynnea Lobert
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Douglas Mahoney
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Brent Johnston
- Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
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Hasanpour Segherlou Z, Nouri-Vaskeh M, Noroozi Guilandehi S, Baghbanzadeh A, Zand R, Baradaran B, Zarei M. GDF-15: Diagnostic, prognostic, and therapeutic significance in glioblastoma multiforme. J Cell Physiol 2021; 236:5564-5581. [PMID: 33580506 DOI: 10.1002/jcp.30289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/16/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022]
Abstract
Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumor and has a remarkably weak prognosis. According to the aggressive form of GBM, understanding the accurate molecular mechanism associated with GBM pathogenesis is essential. Growth differentiation factor 15 (GDF-15) belongs to transforming growth factor-β superfamily with important roles to control biological processes. It affects cancer growth and progression, drug resistance, and metastasis. It also can promote stemness in many cancers, and also can stress reactions control, bone generation, hematopoietic growth, adipose tissue performance, and body growth, and contributes to cardiovascular disorders. The role GDF-15 to develop and progress cancer is complicated and remains unclear. GDF-15 possesses tumor suppressor properties, as well as an oncogenic effect. GDF-15 antitumorigenic and protumorigenic impacts on tumor development are linked to the cancer type and stage. However, the GDF-15 signaling and mechanism have not yet been completely identified because of no recognized cognate receptor.
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Affiliation(s)
| | - Masoud Nouri-Vaskeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Zand
- Department of Neurology, Geisinger Health System, Danville, Pennsylvania, USA
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Zarei
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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YOSHIMURA A, AKI D, ITO M. SOCS, SPRED, and NR4a: Negative regulators of cytokine signaling and transcription in immune tolerance. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2021; 97:277-291. [PMID: 34121041 PMCID: PMC8403526 DOI: 10.2183/pjab.97.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Cytokines are important intercellular communication tools for immunity. Most cytokines utilize the JAK-STAT and Ras-ERK pathways to promote gene transcription and proliferation; however, this signaling is tightly regulated. The suppressor of cytokine signaling (SOCS) family and SPRED family are a representative negative regulators of the JAK-STAT pathway and the Ras-ERK pathway, respectively. The SOCS family regulates the differentiation and function of CD4+ T cells, CD8+ T cells, and regulatory T cells, and is involved in immune tolerance, anergy, and exhaustion. SPRED family proteins have been shown to inactivate Ras by recruiting the Ras-GTPase neurofibromatosis type 1 (NF1) protein. Human genetic analysis has shown that SOCS family members are strongly associated with autoimmune diseases, allergies, and tumorigenesis, and SPRED1 is involved in NF1-like syndromes and tumors. We also identified the NR4a family of nuclear receptors as a key transcription factor for immune tolerance that suppresses cytokine expression and induces various immuno-regulatory molecules including SOCS1.
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Affiliation(s)
- Akihiko YOSHIMURA
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- Correspondence should be addressed: A. Yoshimura, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan (e-mail: )
| | - Daisuke AKI
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Minako ITO
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
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Ge J, Wang Y, Yan Q, Wu C, Yu H, Yang H, Zou J. FK506 Induces the TGF-β1/Smad 3 Pathway Independently of Calcineurin Inhibition to Prevent Intervertebral Disk Degeneration. Front Cell Dev Biol 2020; 8:608308. [PMID: 33363168 PMCID: PMC7758291 DOI: 10.3389/fcell.2020.608308] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/23/2020] [Indexed: 01/07/2023] Open
Abstract
Background Intervertebral disk (IVD) degeneration is the most common cause of lower back pain. Inhibiting inflammation is a key strategy for delaying IVD degeneration. Tacrolimus (FK506) is a potent immunosuppressive agent that is also beneficial to chondrocytes via alleviating inflammation. However, the potential function of FK506 in IVD and the underlying mechanisms remain unknown. The current study is aim at exploring the underlying mechanism of FK506 in preventing IVD degeneration. Methods Cell morphology was imaged using an optical microscope. mRNA levels of nucleus pulposus (NP) matrix components were determined by qRT-PCR, and protein expression NP matrix components was assessed by western blotting. A rat caudal IVD degeneration model was established to test for FK506 in vivo. Results FK506 improved the morphology of NP cells and the cell function at both the mRNA and protein level. FK506 could attenuate NP degeneration induced by IL-1β. Furthermore, FK506 exerted its function via TGFβ/Smad3 activation instead of through calcineurin inhibition. Inhibition of the TGF-β pathway prevented the protective effect of FK506 on IVD degeneration. In an in vivo study, FK506 injection reversed the development of rat caudal IVD degeneration influenced by Smad3. Conclusion Our current study demonstrates the positive effect of FK506 on delaying the degeneration of IVD via the TGFβ/Smad3 pathway.
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Affiliation(s)
- Jun Ge
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yingjie Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qi Yan
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cenhao Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hao Yu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huilin Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Zou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Owyang SY, Zhang M, El-Zaatari M, Eaton KA, Bishu S, Hou G, Grasberger H, Kao JY. Dendritic cell-derived TGF-β mediates the induction of mucosal regulatory T-cell response to Helicobacter infection essential for maintenance of immune tolerance in mice. Helicobacter 2020; 25:e12763. [PMID: 33025641 PMCID: PMC7885176 DOI: 10.1111/hel.12763] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/04/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori infection leads to regulatory T-cell (Treg) induction in infected mice, which contributes to H. pylori immune escape. However, the mechanisms responsible for H. pylori induction of Treg and immune tolerance remain unclear. We hypothesized DC-produced TGF-β may be responsible for Treg induction and immune tolerance. MATERIALS AND METHODS To test this hypothesis, we generated TGF-β∆DC mice (CD11c+ DC-specific TGF-β deletion) and assessed the impact of DC-specific TGF-β deletion on DC function during Helicobacter infection in vitro and in vivo. To examine the T cell-independent DC function, we crossed TGF-β∆DC mice onto Rag1KO background to generate TGF-β∆DC xRag1KO mice. RESULTS When stimulated with H. pylori, TGF-β∆DC BMDC/splenocyte cocultures showed increased levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines compared to control, indicating a proinflammatory DC phenotype. Following 6 months of H. felis infection, TGF-β∆DC mice developed more severe gastritis and a trend toward more metaplasia compared to TGF-βfl/fl with increased levels of inflammatory Th1 cytokine mRNA and lower gastric H. felis colonization compared to infected TGF-βfl/fl mice. In a T cell-deficient background using TGF-β∆DC xRag1KO mice, H. felis colonization was significantly lower when DC-derived TGF-β was absent, revealing a direct, innate function of DC in controlling H. felis infection independent of Treg induction. CONCLUSIONS Our findings indicate that DC-derived TGF-β mediates Helicobacter-induced Treg response and attenuates the inflammatory Th1 response. We also demonstrated a previously unrecognized innate role of DC controlling Helicobacter colonization via a Treg-independent mechanism. DC TGF-β signaling may represent an important target in the management of H. pylori.
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Affiliation(s)
- Stephanie Y. Owyang
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Min Zhang
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Mohamad El-Zaatari
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Kathryn A. Eaton
- Unit for Laboratory Animal Medicine and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, 48109 USA
| | - Shrinivas Bishu
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Guoqing Hou
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - Helmut Grasberger
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
| | - John Y. Kao
- Department of Internal Medicine (Division of Gastroenterology), University of Michigan Health System, Ann Arbor, Michigan, 48109 USA
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López de Andrés J, Griñán-Lisón C, Jiménez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol 2020; 13:136. [PMID: 33059744 PMCID: PMC7559894 DOI: 10.1186/s13045-020-00966-3] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer stem cells (CSCs) represent a tumor subpopulation responsible for tumor metastasis and resistance to chemo- and radiotherapy, ultimately leading to tumor relapse. As a consequence, the detection and eradication of this cell subpopulation represent a current challenge in oncology medicine. CSC phenotype is dependent on the tumor microenvironment (TME), which involves stem and differentiated tumor cells, as well as different cell types, such as mesenchymal stem cells, endothelial cells, fibroblasts and cells of the immune system, in addition to the extracellular matrix (ECM), different in composition to the ECM in healthy tissues. CSCs regulate multiple cancer hallmarks through the interaction with cells and ECM in their environment by secreting extracellular vesicles including exosomes, and soluble factors such as interleukins, cytokines, growth factors and other metabolites to the TME. Through these factors, CSCs generate and activate their own tumor niche by recruiting stromal cells and modulate angiogenesis, metastasis, resistance to antitumor treatments and their own maintenance by the secretion of different factors such as IL-6, VEGF and TGF-ß. Due to the strong influence of the CSC secretome on disease development, the new antitumor therapies focus on targeting these communication networks to eradicate the tumor and prevent metastasis, tumor relapse and drug resistance. This review summarizes for the first time the main components of the CSC secretome and how they mediate different tumor processes. Lastly, the relevance of the CSC secretome in the development of more precise and personalized antitumor therapies is discussed.
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Affiliation(s)
- Julia López de Andrés
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100, Granada, Spain.,Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100, Granada, Spain.,Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Carmen Griñán-Lisón
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100, Granada, Spain.,Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100, Granada, Spain.,Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Gema Jiménez
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100, Granada, Spain. .,Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100, Granada, Spain. .,Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain. .,Department of Health Sciences, University of Jaén, 23071, Jaén, Spain.
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, 18100, Granada, Spain. .,Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100, Granada, Spain. .,Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain. .,Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, 18016, Granada, Spain.
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Li Y, Li J, Dong J, Zhang L, Liu D, He J, She Y, Ma C, Liu Y. 15-PGDH Expression in Gastric Cancer: A Potential Role in Anti-Tumor Immunity. Cancer Manag Res 2020; 12:7419-7426. [PMID: 32884353 PMCID: PMC7443415 DOI: 10.2147/cmar.s245726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 07/30/2020] [Indexed: 11/23/2022] Open
Abstract
Introduction Host immunity plays a vital role in tumorigenesis, including in tumor invasion and metastasis. However, the precise underlying mechanism remains to be explored. The enzyme 15-PGDH, which plays a key role in prostaglandin degradation, is a critical inflammatory mediator in gastric cancer (GC) tumorigenesis. Materials and Methods Immunohistochemistry was performed to determine 15-PGDH expression in GC and the corresponding adjacent non-neoplastic tissues (n=92). Results The expression of 15-PGDH in GC tissues was significantly lower than that in paracancerous tissues (P<0.001) and found to correspond inversely with GC differentiation (P=0.043) and lymph node metastasis (P=0.046). In contrast, FOXP3 expression was increased in poorly differentiated GC tissues (P=0.001). Kaplan–Meier analysis revealed that GC patients with low expression of 15-PGDH (Log rank test, P=0.007) and high expression of FOXP3 (Log rank test, P=0.009) had shorter overall survival (OS) than those with high 15-PGDH and low FOXP3 expression. OS was also correlated with pathological tumor-node-metastasis stage (Log rank test, P=0.014). Furthermore, using Cox proportional hazard regression, 15-PGDH expression [hazard ratio (HR): 0.605 (0.440–0.833); P=0.002] was identified as an independent factor for OS. Conclusion Our data suggest that 15-PGDH may contribute to anti-tumor immunity by regulating FOXP3+ Treg cells. The findings are useful for the identification of therapeutic targets for the management of GC.
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Affiliation(s)
- Yaling Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
| | - Junjie Li
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Juanjuan Dong
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Lei Zhang
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Dongling Liu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Jianzheng He
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
| | - Yali She
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Chengxu Ma
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China
| | - Yongqi Liu
- Provincial-Level Key Laboratory of Molecular Medicine of Major Diseases and Study on Prevention and Treatment of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People's Republic of China.,Key Laboratory of Dunhuang Medicine and Transformation Constructed by Chinese Ministry of Education and Gansu Province, Lanzhou, Gansu, People's Republic of China
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Tu L, Sun X, Yang L, Zhang T, Zhang X, Li X, Dong B, Liu Y, Yang M, Wang L, Yu Y. TGF-β2 interfering oligonucleotides used as adjuvants for microbial vaccines. J Leukoc Biol 2020; 108:1673-1692. [PMID: 32794350 DOI: 10.1002/jlb.5a0420-491r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 04/28/2020] [Accepted: 06/27/2020] [Indexed: 12/12/2022] Open
Abstract
The success of using immune checkpoint inhibitors to treat cancers implies that inhibiting an immunosuppressive cytokine, such as TGF-β2, could be a strategy to develop novel adjuvants for microbial vaccines. To develop nucleic acid based TGF-β2 inhibitors, we designed three antisense oligonucleotides, designated as TIO1, TIO2, and TIO3, targeting the conserve regions identical in human and mouse TGF-β2 mRNA 3'-untranslated region. In cultured immune cells, TIO3 and TIO1 significantly reduced the TGF-β2 mRNA expression and protein production. In mice, the TIO3 and TIO1, when formulated in various microbial vaccines, significantly enhanced the antibody response to the vaccines, and the TIO3-adjuvanted influenza virus vaccine induced effective protection against the influenza virus challenge. In the immunized mice, TIO3 formulated in microbial vaccines dramatically reduced surface-bound TGF-β2 expression on CD4+ T cells and CD19+ B cells in the lymph node (LN) cells and spleen cells; up-regulated the expression of CD40, CD80, CD86, and MHC II molecules on CD19+ B cells and CD11c+ dendritic cells; and promoted IFN-γ production in CD4+ T cells and CD8+ T cells in the LN cells. Overall, TIO3 or TIO1 could be used as a novel type of adjuvant for facilitating the microbial vaccines to elicit more vigorous and persistent antibody response by interfering with TGF-β2 expression.
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Affiliation(s)
- Liqun Tu
- Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Xiaomeng Sun
- Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Lei Yang
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Tiefeng Zhang
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Xian Zhang
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Xin Li
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Boqi Dong
- Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Ye Liu
- Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Ming Yang
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Liying Wang
- Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
| | - Yongli Yu
- Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun, Jilin, China
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Marhemati F, Rezaei R, Mohseni Meybodi A, Taheripanah R, Mostafaei S, Amani D. Transforming growth factor beta 1 (TGFβ1) polymorphisms and unexplained infertility: A genetic association study. Syst Biol Reprod Med 2020; 66:267-280. [PMID: 32735465 DOI: 10.1080/19396368.2020.1773575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The prevalence of infertility is increasing and worrisome. About 10 to 30% of infertility is classified as idiopathic or unexplained infertility (UI).TGF-β is multifunctional and immunoregulatry cytokine which regulates both implantation and adhesion of trophoblasts to the extracellular matrix during pregnancy. The aim of the current study was to investigate the association between two polymorphisms rs1800470 (C29T) and rs1800471 (G74C) of the TGF-β1 gene in Iranian patients with unexplained infertility. A total of 250 UI patients and 484 healthy individuals with no history of infertility were included in the study. The amplification and sequencing of target DNA fragments were done using PCR and automated sequencing methods, respectively. The effects of these polymorphisms on both TGF-β1 structure and function of mRNA and protein were analyzed using new in-silico tools. The frequency distribution of the alleles, genotypes, and haplotypes of both rs1800470 and rs1800471 polymorphisms had a statistically significant difference between subjects and controls. CC genotype of TGF-β1 rs1800470 (29C→T) increase the risk of UI in male UI patients. Moreover, C alleles of TGF-β1 rs1800471 was associated with increased risk of UI in female UI patients. Couples, subgroup analysis revealed a significant association between TGF-β1 polymorphisms (rs1800470, rs1800471) and the risk of UI in male, female, and all UI patients. The frequency of TG and CG haplotypes were statistically different in both UI and healthy subjects group (P < 0.05). RS1800471 polymorphisms changed the secondary structure of TGF-β1 mRNA and resulted in the removal of one mRNA arm and creation of two new arms. Taken together, the results of the current study suggest that TGF-β1 functional polymorphisms may play an important role in the susceptibility to UI in Iranian population. According to in silico analysis, polymorphisms in TGF-β1 can reduce mRNA half-life and, therefore, reduced TGF-β1 expression. .
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Affiliation(s)
- Farnaz Marhemati
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran, Iran
| | - Ramazan Rezaei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran, Iran
| | - Anahita Mohseni Meybodi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR , Tehran, Iran
| | - Robabeh Taheripanah
- Department of Gynecology and Obstetrics, Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences , Tehran, Iran
| | - Shayan Mostafaei
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences , Kermanshah, Iran.,Epidemiology and Biostatistics Unit, Rheumatology Research Center, Tehran University of Medical Sciences , Tehran, Iran
| | - Davar Amani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran, Iran.,Department of Gynecology and Obstetrics, Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences , Tehran, Iran
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Imura Y, Ando M, Kondo T, Ito M, Yoshimura A. CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. JCI Insight 2020; 5:136185. [PMID: 32525846 DOI: 10.1172/jci.insight.136185] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 06/04/2020] [Indexed: 12/24/2022] Open
Abstract
Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human PBMCs (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127loCD45RA+CD45RO-. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production and differentiation of B cells via a TGF-β-dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs, reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.
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Affiliation(s)
- Yuki Imura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.,Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corp., Yokohama, Japan
| | - Makoto Ando
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Taisuke Kondo
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.,Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Minako Ito
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
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Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis. Biomedicines 2020; 8:biomedicines8070226. [PMID: 32708498 PMCID: PMC7400438 DOI: 10.3390/biomedicines8070226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 01/30/2023] Open
Abstract
Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significant increase in the percentage of GM-CSF-expressing Th cells, Th1 cells, Th-GM cells, cytotoxic T (Tc) cells, monocytes, natural killer (NK) cells, and B cells in PBMC from MS patients stimulated with T cell stimuli. Stimulated PBMC culture supernatants from MS patients contained significantly higher levels of IL-2, IL-12, IL-1β, and GM-CSF and significantly lower levels of transforming growth factor (TGF-)β. Blocking IL-2 reduced the frequency of Th-GM cells in PBMC from MS patients. The frequency of Th-GM cells differentiated in vitro from naïve CD4+ T cells was significantly higher in MS patients and was further increased in MS with IL-2 stimulation. These findings suggest that all main immune cell subsets produce more GM-CSF in MS after in vitro stimulation, which is associated with defective TGF-β and increased IL-2 and IL-12 production. Th-GM cells are increased in MS. GM-CSF may be a potential therapeutic target in MS.
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Janikowska G, Kurzeja E, Janikowski M, Strzałka-Mrozik B, Pyka-Pająk A, Janikowski T. The Effect of Cyclosporine A on Dermal Fibroblast Cell - Transcriptomic Analysis of Inflammatory Response Pathway. Curr Pharm Biotechnol 2020; 21:1213-1223. [PMID: 32297577 DOI: 10.2174/1389201021666200416103928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND The first immunosuppressive drug - cyclosporine A (CsA) has many unquestioned merits in maintaining organ transplants in patients, as well as, in the treatment of many inflammatory diseases, also associated with cutaneous manifestations. The main task of this drug is to suppress the inflammatory response at the sites of action, which is not well known. OBJECTIVE The objective of this study was to evaluate the influence of CsA in therapeutic concentration on the expression of genes associated with the inflammatory response pathway in normal human dermal fibroblasts (NHDF; CC-2511), and this study attempted to determine the mechanism of its action. METHODS The cytotoxicity MTT test was performed. The expression of the inflammatory response pathway genes was determined using HG-U133A_2.0 oligonucleotide microarrays. Statistical analysis was performed by GeneSpring 13.0 software using the PL-Grid platform. RESULTS Among the 5,300 mRNA, only 573 were changed significantly in response to CsA compared to the control fibroblasts (P≤0.05). CsA inhibited the expression of most genes associated with the inflammatory response in NHDFs. There were only 19 genes with a fold change (FC) lower than -2.0, among which EGR1, FOS, PBK, CDK1 and TOP2A had the lowest expression, as did CXCL2 which can directly impact inflammation. Furthermore, ZNF451 was strongly induced, and COL1A1, COL3A1, IL33, TNFRSFs were weakly up-regulated (FC lower than 2.0). CONCLUSION The CsA in therapeutic concentration influences the genes linked to the inflammatory response (in the transcriptional level) in human dermal fibroblasts. The findings suggest that the potential mechanism of CsA action in this concentration and on these genes can be associated with a profibrotic and proapoptotic, and genotoxic effects.
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Affiliation(s)
- Grażyna Janikowska
- Department of Analytical Chemistry, Medical University of Silesia in Katowice, Katowice, Poland
| | - Ewa Kurzeja
- Department of Analytical Chemistry, Medical University of Silesia in Katowice, Katowice, Poland
| | - Marcin Janikowski
- Student Scientific Club at the Department of Molecular Biology, Medical University of Silesia in Katowice, Katowice, Poland
| | | | - Alina Pyka-Pająk
- Department of Analytical Chemistry, Medical University of Silesia in Katowice, Katowice, Poland
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Heintz MM, McRee R, Kumar R, Baldwin WS. Gender differences in diet-induced steatotic disease in Cyp2b-null mice. PLoS One 2020; 15:e0229896. [PMID: 32155178 PMCID: PMC7064244 DOI: 10.1371/journal.pone.0229896] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 02/16/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease; however, progression to nonalcoholic steatohepatitis (NASH) is associated with most adverse outcomes. CYP2B metabolizes multiple xeno- and endobiotics, and male Cyp2b-null mice are diet-induced obese (DIO) with increased NAFLD. However, the DIO study was not performed long enough to assess progression to NASH. Therefore, to assess the role of Cyp2b in fatty liver disease progression from NAFLD to NASH, we treated wildtype (WT) and Cyp2b-null mice with a normal diet (ND) or choline-deficient, L-amino acid-defined high fat diet (CDAHFD) for 8 weeks and determined metabolic and molecular changes. CDAHFD-fed WT female mice gained more weight and had greater liver and white adipose tissue mass than their Cyp2b-null counterparts; males experienced diet-induced weight loss regardless of genotype. Serum biomarkers of liver injury increased in both CDAHFD-fed female and male mice; however CDAHFD-fed Cyp2b-null females exhibited significantly lower serum ALT, AST, and ASP concentrations compared to WT mice, indicating Cyp2b-null females were protected from liver injury. In both genders, hierarchical clustering of RNA-seq data demonstrates several gene ontologies responded differently in CDAHFD-fed Cyp2b-null mice compared to WT mice (lipid metabolism > fibrosis > inflammation). Oil Red O staining and direct triglycerides measurements confirmed that CDAHFD-fed Cyp2b-null females were protected from NAFLD. CDAHFD-fed Cyp2b-null mice showed equivocal changes in fibrosis with transcriptomic and serum markers suggesting less inflammation due to glucocorticoid-mediated repression of immune responses. In contrast to females, CDAHFD-fed Cyp2b-null males had higher triglyceride levels. Results indicate that female Cyp2b-null mice are protected from NAFLD while male Cyp2b-null mice are more susceptible to NAFLD, with few significant changes in NASH development. This study confirms that increased NAFLD development does not necessarily lead to progressive NASH. Furthermore, it indicates a role for Cyp2b in fatty liver disease that differs based on gender.
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Affiliation(s)
- Melissa M. Heintz
- Environmental Toxicology Program, Clemson University, Clemson, SC, United States of America
- Biological Sciences, Clemson University, Clemson, SC, United States of America
| | - Rebecca McRee
- Biological Sciences, Clemson University, Clemson, SC, United States of America
| | - Ramiya Kumar
- Biological Sciences, Clemson University, Clemson, SC, United States of America
| | - William S. Baldwin
- Environmental Toxicology Program, Clemson University, Clemson, SC, United States of America
- Biological Sciences, Clemson University, Clemson, SC, United States of America
- * E-mail:
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