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Zhang R, Qiao H, Zhou K, Ju X, Cao X, Dong J, Wu M, Yu L, Zhang S. An immune-based predictive model for HBV clearance: validation in multicenter cohorts and mechanistic insights from in vivo studies. Virol J 2025; 22:153. [PMID: 40399947 PMCID: PMC12096729 DOI: 10.1186/s12985-025-02792-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Chronic HBV infection is a major risk factor for hepatocellular carcinoma, posing a significant global health burden. However, predictive models for HBV clearance based on immune biomarkers remain limited. METHODS We systematically developed a predictive tool by quantifying mRNA expression levels of CD4⁺ T-cell subset transcription factors, cytokines, and immune checkpoints in PBMCs from chronic HBV patients and resolved HBV individuals using RT-qPCR. A binary logistic regression model was constructed in the training cohort, with performance evaluated by ROC and calibration curves, followed by internal and external validation in independent cohorts. For in vivo validation, an HBV-transfected mouse model was established via rapid tail vein injection of pGL3-CP-Fluc-HBV1.2C2 plasmid. Outcomes included body weight, HBsAg/HBV DNA levels, and luciferase activity. Kaplan-Meier analysis assessed cumulative clearance rates, while RT-qPCR tracked model-related mRNA dynamics in PBMCs. RESULTS The model identified GATA3, FOXP3, IFNG, TNF, and HAVCR2 as key genes, demonstrating robust predictive accuracy for HBV clearance. Dose-specific temporal patterns of immune gene regulation were observed, revealing distinct immunomodulatory mechanisms between groups. CONCLUSION This study establishes a reliable immune-based predictive model for HBV clearance and highlights divergent immune responses in chronic versus resolved infection.
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Affiliation(s)
- Rongzheng Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Han Qiao
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Kun Zhou
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
- Department of Clinical Laboratory, Beidahuang Industry Group General Hospital, Harbin, 150000, China
| | - Xiaomei Ju
- Department of Clinical Laboratory, The First Clinical Hospital of Jilin Academy of Traditional Chinese Medicine, Changchun, 130000, China
| | - Xinyang Cao
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Jianming Dong
- Department of Immunology, Harbin Medical University, Harbin, 150000, China
| | - Meng Wu
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Le Yu
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Shuyun Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China.
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Sá-Pessoa J, Calderón-González R, Lee A, Bengoechea JA. Klebsiella pneumoniae emerging anti-immunology paradigms: from stealth to evasion. Trends Microbiol 2025; 33:533-545. [PMID: 39884872 DOI: 10.1016/j.tim.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/27/2024] [Accepted: 01/13/2025] [Indexed: 02/01/2025]
Abstract
Klebsiella pneumoniae (KP) is a global threat to human health due to the isolation of multidrug-resistant strains. Despite advancements in understanding KP's population structure, antibiotic resistance mechanisms, and transmission patterns, a gap remains in how KP evades defenses, allowing the pathogen to flourish in tissues despite an activated immune system. KP infection biology has been shaped by the notion that the pathogen has evolved to shield from defenses more than actively suppress them. This review describes new paradigms of how KP exploits the coevolution with the innate immune system to hijack immune effectors and receptors to ablate signaling pathways and to counteract cell-intrinsic immunity, making apparent that KP can no longer be considered only as a stealth pathogen.
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Affiliation(s)
- Joana Sá-Pessoa
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Ricardo Calderón-González
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - Alix Lee
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK
| | - José A Bengoechea
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, UK.
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Viramontes KM, Thone MN, De La Torre JJ, Neubert EN, DeRogatis JM, Garcia C, Henriquez ML, Tinoco R. Contrasting roles of PSGL-1 and PD-1 in regulating T-cell exhaustion and function during chronic viral infection. J Virol 2025; 99:e0224224. [PMID: 39912665 PMCID: PMC11915808 DOI: 10.1128/jvi.02242-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 01/19/2025] [Indexed: 02/07/2025] Open
Abstract
Immune checkpoints are critical regulators of T-cell exhaustion, impairing their ability to eliminate antigens present during chronic viral infections. Current immune checkpoint inhibitors (ICIs) used in the clinic aim to reinvigorate exhausted T cells; yet, most patients fail to respond or develop resistance to these therapies, underscoring the need to better understand these immunosuppressive pathways. PSGL-1 (Selplg), a recently discovered immune checkpoint, negatively regulates T-cell function. We investigated the cell-intrinsic effects of PSGL-1, PD-1, and combined deletion on CD8+ T cells during chronic viral infection. We found that combined PSGL-1 and PD-1 (Selplg-/-Pdcd1-/-) deficiency in CD8+ T cells increased their frequencies and numbers throughout chronic infection compared to the wild type. This phenotype was primarily driven by PD-1 deficiency. Furthermore, while PD-1 deletion increased virus-specific T-cell frequencies, it was detrimental to their function. Conversely, PSGL-1 deletion improved T-cell function but resulted in lower frequencies and numbers. The primary mechanism behind these differences in cell maintenance was driven by proliferation rather than survival. Combined PSGL-1 and PD-1 deletion resulted in defective T-cell differentiation, driving cells from a progenitor self-renewal state to a more terminal dysfunctional state. These findings suggest that PD-1 and PSGL-1 have distinct, yet complementary, roles in regulating T-cell exhaustion and differentiation during chronic viral infection. Overall, this study provides novel insights into the individual and combined roles of PSGL-1 and PD-1 in CD8+ T-cell exhaustion. It underscores the potential of targeting these checkpoints in a more dynamic and sequential manner to optimize virus-specific T-cell responses, offering critical perspectives for improving therapeutic strategies aimed at reinvigorating exhausted CD8+ T cells.IMPORTANCEOur findings provide a comprehensive analysis of how the dual deletion of PD-1 and PSGL-1 impacts the response and function of virus-specific CD8+ T cells, revealing novel insights into their roles in chronic infection. Notably, our findings show that while PD-1 deletion enhances T-cell frequencies, it paradoxically reduces T-cell functionality. Conversely, PSGL-1 deletion improves T-cell function but reduces their survival. Whereas the combined deletion of PSGL-1 and PD-1 in CD8+ T cells improved their survival but decreased their function and progenitor-exhausted phenotypes during infection. We believe our study advances the understanding of immune checkpoint regulation in chronic infections and has significant implications for developing more effective immune checkpoint inhibitor (ICI) therapies.
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Affiliation(s)
- Karla M. Viramontes
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Melissa N. Thone
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Jamie-Jean De La Torre
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Emily N. Neubert
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Julia M. DeRogatis
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Chris Garcia
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Monique L. Henriquez
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Roberto Tinoco
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
- Center for Virus Research, University of California Irvine, Irvine, California, USA
- Institute for Immunology, University of California Irvine, Irvine, California, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA
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Xu Q, Li L, Zhu R. T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker? Curr Allergy Asthma Rep 2025; 25:18. [PMID: 40091122 DOI: 10.1007/s11882-025-01199-5] [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] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
PURPOSE OF REVIEW This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy. RECENT FINDINGS Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.
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Affiliation(s)
- Qingxiu Xu
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Le Li
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Rongfei Zhu
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Kastner AL, Marx AF, Dimitrova M, Abreu-Mota T, Ertuna YI, Bonilla WV, Stauffer K, Künzli M, Wagner I, Kreutzfeldt M, Merkler D, Pinschewer DD. Durable lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection. Immunity 2025; 58:481-498.e10. [PMID: 39719711 DOI: 10.1016/j.immuni.2024.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/02/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024]
Abstract
To interrogate the role of specific immune cells in infection, cancer, and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods, we engineered adeno-associated viral vectors expressing depletion mAbs (depletion-AAVs). Single-dose depletion-AAV administration durably eliminated lymphocyte subsets in mice and avoided accessory deficiencies of GEMMs, such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used in animals of different genetic backgrounds, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we showed that B cells were required for unimpaired CD4+ and CD8+ T cell responses to chronic lymphocytic choriomeningitis virus (LCMV) infection. Upon B cell depletion, CD8+ T cells failed to suppress viremia, and they only helped resolve chronic infection when antibodies dampened viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.
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Affiliation(s)
- Anna Lena Kastner
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | | | - Mirela Dimitrova
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | - Tiago Abreu-Mota
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | - Yusuf I Ertuna
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | - Weldy V Bonilla
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | - Karsten Stauffer
- Department of Biomedicine, University of Basel, 4009 Basel, Switzerland
| | - Marco Künzli
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
| | - Ingrid Wagner
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland
| | - Mario Kreutzfeldt
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1206 Geneva, Switzerland
| | - Doron Merkler
- Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1206 Geneva, Switzerland
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Ali AA, Tabll AA. Unlocking potential: Virus-like particles as a promising strategy for effective HCV vaccine development. Virology 2025; 602:110307. [PMID: 39580887 DOI: 10.1016/j.virol.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of prophylactic vaccine is essential for HCV global eradication. Despite over three decades of research, no effective vaccine for HCV has been developed, primarily due to the virus's genetic diversity, immune evasion mechanisms, and incomplete understanding of protective immunity. However, Virus-Like Particles (VLPs) offer a promising approach to overcoming these challenges. VLPs mimic the structure of native virus but without the infectious genome, making them safe and non-infectious vaccines candidates. The capability of VLPs to incorporate neutralizing and conformational epitopes, and engage humoral and cellular immune responses, positions them as a promising tool for overcoming challenges associated with the HCV vaccine development. This review examines the challenges and immunological considerations for HCV vaccine development and provides an overview of the VLPs-based vaccines development. It also discusses future directions and public health implications of HCV vaccine development.
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Affiliation(s)
- Ahmed A Ali
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, (NRC), 12622, Cairo, Egypt.
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, 12622, Cairo, Egypt; Egyptian Centre for Research and Regenerative Medicine (ECRRM), 11517, Cairo, Egypt.
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7
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Zhang W, Yu Q, Gao X, Chen H, Su J, Chen Y, Li Y, Zhang N, Fu Z, Cui M. Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8 + T Cells during JEV Infection. Int J Biol Sci 2024; 20:5959-5978. [PMID: 39664572 PMCID: PMC11628328 DOI: 10.7150/ijbs.102372] [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: 08/15/2024] [Accepted: 10/18/2024] [Indexed: 12/13/2024] Open
Abstract
Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), is a mosquito-borne zoonotic disease and a leading cause of viral encephalitis worldwide. While JEV has the ability to traverse the blood-brain barrier (BBB), the precise mechanisms by which it inhibits the immune response prior to penetrating the BBB remain unclear, presenting obstacles in the development of efficacious therapeutic interventions. This study investigated the impact of JEV on CD8+ T cell responses, with a particular focus on the dysfunction of CD8+ T cells during JEV infection. Our results demonstrated that JEV infection significantly elevated the expression of PD-1 and TIM-3 on CD8+ T cells, which are markers of T cell exhaustion, leading to inhibited function and impaired differentiation, resulting in a poorer prognosis in mice. Compared with nondiseased mice, symptomatic mice presented a greater proportion of exhaustion-like CD8+ T cells. In vitro experiments further demonstrated that MDSCs induced an exhaustion-like state in CD8+ T cells, characterized by significant upregulation of PD-1 and TIM-3 expression. Notably, blocking TIM-3 or depleting MDSCs restored CD8+ T cell functionality by rescuing the expression of IFN-γ and TNF-α. Furthermore, the depletion of MDSCs not only alleviated T cell exhaustion-like phenotypes but also improved survival rates in JEV-infected mice. These findings suggest that JEV promotes immune evasion through MDSC-induced CD8+ T cell exhaustion-like states and identify TIM-3 as a promising therapeutic target for JE treatment.
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Affiliation(s)
- Weijia Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Qing Yu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Xiaochen Gao
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Haowei Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Jie Su
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanru Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Yanling Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Nan Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Zhenfang Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
| | - Min Cui
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Centre for Sustainable Pig Production, Wuhan, China
- Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, China
- International Research Centre for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China
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Gu Q, Yin S, Tong X, Rui F, Zhu Y, Ma X, Huang R, Wu C, Li J. Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection. J Viral Hepat 2024; 31:557-564. [PMID: 38771314 DOI: 10.1111/jvh.13958] [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: 01/11/2024] [Revised: 04/29/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Qi Gu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Fajuan Rui
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yixuan Zhu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyan Ma
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
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Zhao J, Wang Z, Tian Y, Ning J, Ye H. T cell exhaustion and senescence for ovarian cancer immunotherapy. Semin Cancer Biol 2024; 104-105:1-15. [PMID: 39032717 DOI: 10.1016/j.semcancer.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 07/23/2024]
Abstract
Ovarian cancer is a common gynecological malignancy, and its treatment remains challenging. Although ovarian cancer may respond to immunotherapy because of endogenous immunity at the molecular or T cell level, immunotherapy has so far not had the desired effect. The functional status of preexisting T cells is an indispensable determinant of powerful antitumor immunity and immunotherapy. T cell exhaustion and senescence are two crucial states of T cell dysfunction, which share some overlapping phenotypic and functional features, but each status possesses unique molecular and developmental signatures. It has been widely accepted that exhaustion and senescence of T cells are important strategies for cancer cells to evade immunosurveillance and maintain the immunosuppressive microenvironment. Herein, this review summarizes the phenotypic and functional features of exhaust and senescent T cells, and describes the key drivers of the two T cell dysfunctional states in the tumor microenvironment and their functional roles in ovarian cancer. Furthermore, we present a summary of the molecular machinery and signaling pathways governing T cell exhaustion and senescence. Possible strategies that can prevent and/or reverse T cell dysfunction are also explored. An in-depth understanding of exhausted and senescent T cells will provide novel strategies to enhance immunotherapy of ovarian cancer through redirecting tumor-specific T cells away from a dysfunctional developmental trajectory.
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Affiliation(s)
- Jiao Zhao
- Department of Gynecology Surgery 3, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Zhongmiao Wang
- Department of Digestive Diseases 1, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Yingying Tian
- Department of Oncology Radiotherapy 2, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong 266042, China
| | - Jing Ning
- Department of General Internal Medicine (VIP Ward), Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Huinan Ye
- Department of Digestive Diseases 1, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
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Fan Q, Wang Y, Cheng J, Pan B, Zang X, Liu R, Deng Y. Single-cell RNA-seq reveals T cell exhaustion and immune response landscape in osteosarcoma. Front Immunol 2024; 15:1362970. [PMID: 38629071 PMCID: PMC11018946 DOI: 10.3389/fimmu.2024.1362970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
Background T cell exhaustion in the tumor microenvironment has been demonstrated as a substantial contributor to tumor immunosuppression and progression. However, the correlation between T cell exhaustion and osteosarcoma (OS) remains unclear. Methods In our present study, single-cell RNA-seq data for OS from the GEO database was analysed to identify CD8+ T cells and discern CD8+ T cell subsets objectively. Subgroup differentiation trajectory was then used to pinpoint genes altered in response to T cell exhaustion. Subsequently, six machine learning algorithms were applied to develop a prognostic model linked with T cell exhaustion. This model was subsequently validated in the TARGETs and Meta cohorts. Finally, we examined disparities in immune cell infiltration, immune checkpoints, immune-related pathways, and the efficacy of immunotherapy between high and low TEX score groups. Results The findings unveiled differential exhaustion in CD8+ T cells within the OS microenvironment. Three genes related to T cell exhaustion (RAD23A, SAC3D1, PSIP1) were identified and employed to formulate a T cell exhaustion model. This model exhibited robust predictive capabilities for OS prognosis, with patients in the low TEX score group demonstrating a more favorable prognosis, increased immune cell infiltration, and heightened responsiveness to treatment compared to those in the high TEX score group. Conclusion In summary, our research elucidates the role of T cell exhaustion in the immunotherapy and progression of OS, the prognostic model constructed based on T cell exhaustion-related genes holds promise as a potential method for prognostication in the management and treatment of OS patients.
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Affiliation(s)
- Qizhi Fan
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yiyan Wang
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jun Cheng
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Boyu Pan
- Department of Orthopedics, Third Hospital of Changsha, Changsha, China
| | - Xiaofang Zang
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Renfeng Liu
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Youwen Deng
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
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11
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Calderon-Gonzalez R, Dumigan A, Sá-Pessoa J, Kissenpfennig A, Bengoechea JA. In vivo single-cell high-dimensional mass cytometry analysis to track the interactions between Klebsiella pneumoniae and myeloid cells. PLoS Pathog 2024; 20:e1011900. [PMID: 38578798 PMCID: PMC11023633 DOI: 10.1371/journal.ppat.1011900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/17/2024] [Accepted: 03/18/2024] [Indexed: 04/07/2024] Open
Abstract
In vivo single-cell approaches have transformed our understanding of the immune populations in tissues. Mass cytometry (CyTOF), that combines the resolution of mass spectrometry with the ability to conduct multiplexed measurements of cell molecules at the single cell resolution, has enabled to resolve the diversity of immune cell subsets, and their heterogeneous functionality. Here we assess the feasibility of taking CyTOF one step further to immuno profile cells while tracking their interactions with bacteria, a method we term Bac-CyTOF. We focus on the pathogen Klebsiella pneumoniae interrogating the pneumonia mouse model. Using Bac-CyTOF, we unveil the atlas of immune cells of mice infected with a K. pneumoniae hypervirulent strain. The atlas is characterized by a decrease in the populations of alveolar and monocyte-derived macrophages. Conversely, neutrophils, and inflammatory monocytes are characterized by an increase in the subpopulations expressing markers of less active cells such as the immune checkpoint PD-L1. These are the cells infected. We show that the type VI secretion system (T6SS) contributes to shape the lung immune landscape. The T6SS governs the interaction with monocytes/macrophages by shifting Klebsiella from alveolar macrophages to interstitial macrophages and limiting the infection of inflammatory monocytes. The lack of T6SS results in an increase of cells expressing markers of active cells, and a decrease in the subpopulations expressing PD-L1. By probing Klebsiella, and Acinetobacter baumannii strains with limited ability to survive in vivo, we uncover that a heightened recruitment of neutrophils, and relative high levels of alveolar macrophages and eosinophils and the recruitment of a characteristic subpopulation of neutrophils are features of mice clearing infections. We leverage Bac-CyTOF-generated knowledge platform to investigate the role of the DNA sensor STING in Klebsiella infections. sting-/- infected mice present features consistent with clearing the infection including the reduced levels of PD-L1. STING absence facilitates Klebsiella clearance.
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Affiliation(s)
- Ricardo Calderon-Gonzalez
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Amy Dumigan
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Joana Sá-Pessoa
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Adrien Kissenpfennig
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - José A. Bengoechea
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
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12
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Yang Y, Wuren T, Wu B, Cheng S, Fan H. The expression of CTLA-4 in hepatic alveolar echinococcosis patients and blocking CTLA-4 to reverse T cell exhaustion in Echinococcus multilocularis-infected mice. Front Immunol 2024; 15:1358361. [PMID: 38605966 PMCID: PMC11007148 DOI: 10.3389/fimmu.2024.1358361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/11/2024] [Indexed: 04/13/2024] Open
Abstract
Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by the infection of Echinococcus multilocularis (E. multilocularis) larvae. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) produces inhibitory signals and induces T cell exhaustion, thereby inhibiting the parasiticidal efficacy of the liver immune system. Therefore, the purpose of this study is to explore how T-cell exhaustion contributes to AE and whether blocking CTLA-4 could reverse T cell exhaustion. Here we discovered that the expression of CTLA-4 was increased in the infiltrating margin around the lesion of the liver from AE patients by using western blot and immunohistochemistry assay. Multiple fluorescence immunohistochemistry identified that CTLA-4 and CD4/CD8 molecules were co-localized. For in vitro experiments, it was found that the sustained stimulation of E. multilocularis antigen could induce T cell exhaustion, blocking CTLA-4-reversed T cell exhaustion. For in vivo experiments, the expression of CTLA-4 was increased in the liver of E. multilocularis-infected mice, and the CTLA-4 and CD4/CD8 molecules were co-localized. Flow cytometry analysis demonstrated that the percentages of both CD4+ T cells and CD8+ T cells in the liver and peripheral blood were significantly increased and induced T exhaustion. When the mice were treated with anti-CTLA-4 antibodies, the number and weight of the lesions decreased significantly. Meanwhile, the flow cytometry results suggested that blocking CTLA-4 could effectively reverse T cell exhaustion and reactivate immune function. Our work reveals that blocking CTLA-4 could effectively reverse the T cell exhaustion caused by E. multilocularis and could be used as a novel target for the treatment of AE.
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Affiliation(s)
- Yuxuan Yang
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
| | - Binjie Wu
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Shilei Cheng
- Research Center for High Altitude Medicine, Qinghai University, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Laboratory for High Altitude Medicine of Qinghai Province, Xining, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
| | - Haining Fan
- Qinghai Research Key Laboratory for Echinococcosis, Qinghai University, Xining, Qinghai, China
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai, China
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13
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Liu Y, Zhao Z, Su S, Li Y, Chen N, He L, Dong M, Xu B, Zhang Z, Zhou Y, Zhu Z. Blockade of BTLA alone or in combination with PD-1 restores the activation and proliferation of CD8 + T cells during in vitro infection with NCP BVDV. Vet Microbiol 2024; 290:110004. [PMID: 38281324 DOI: 10.1016/j.vetmic.2024.110004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/14/2024] [Accepted: 01/17/2024] [Indexed: 01/30/2024]
Abstract
Bovine viral diarrhea virus (BVDV) infection can result in typical peripheral blood lymphopenia and immune dysfunction. However, the molecular mechanism underlying the onset of lymphopenia remains unclear. B and T lymphocyte attenuator (BTLA) is a novel immune checkpoint molecule that primarily inhibits activation and proliferation of T cells. Blockade of BTLA with antibodies can boost the proliferation and anti-viral immune functions of T cells. Nonetheless, the immunomodulatory effects of BTLA in CD8+ T cells during BVDV infection remain unknown. Therefore, BTLA expression was measured in bovine peripheral blood CD8+ T cells infected with BVDV in vitro. Furthermore, the effects of BTLA or PD-1 blockade on CD8+ T cell activation, proliferation, and anti-viral immunological activities were investigated, as well as expression of signaling molecules downstream of BTLA, both alone and in combination. The results demonstrated that BTLA and PD-1 mRNA and protein levels were considerably increased in CD8+ T cells infected with cytopathic and non-cytopathic (NCP) BVDV. Surprisingly, as compared to blockade of either BTLA or PD-1, blockade of both dramatically increased proliferation and expression of CD25 and p-EKR of CD8+ T cells infected with NCP BVDV. Furthermore, blockade of BTLA, but not PD-1, had no effect on BVDV replication or IFN-γ expression. These findings confirmed the immunomodulatory roles of BTLA during BVDV infection, as well as the synergistic role of BTLA and PD-1 in NCP BVDV infection, thereby providing new insights to promote activation and the anti-viral immunological activities of CD8+ T cells.
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Affiliation(s)
- Yu Liu
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China; Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs, Daqing 163319, China; Engineering Research Center of Prevention and Control of Cattle Diseases, Heilongjiang Province, Daqing 163319, China
| | - Zhibo Zhao
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Siyu Su
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Yang Li
- Engineering Research Center of Prevention and Control of Cattle Diseases, Heilongjiang Province, Daqing 163319, China
| | - Nannan Chen
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Linru He
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Meiqi Dong
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Bin Xu
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Zecai Zhang
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Yulong Zhou
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China
| | - Zhanbo Zhu
- College of Animal Science and Veterinary Medicine, HeiLongJiang BaYi Agricultural University, Daqing 163319, China; Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs, Daqing 163319, China; Engineering Research Center of Prevention and Control of Cattle Diseases, Heilongjiang Province, Daqing 163319, China.
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14
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Dong H, Liao Y, Shang M, Fu Y, Zhang H, Luo M, Hu B. Effects of co-infection with Clonorchis sinensis on T cell exhaustion levels in patients with chronic hepatitis B. J Helminthol 2024; 98:e13. [PMID: 38263743 DOI: 10.1017/s0022149x23000871] [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: 01/25/2024]
Abstract
To investigate the effects of co-infection with Clonorchis sinensis (C. sinensis) on T cell exhaustion levels in patients with chronic hepatitis B, we enrolled clinical cases in this study, including the patients with concomitant C. sinensis and HBV infection. In this study, we detected inhibitory receptors and cytokine expression in circulating CD4+ and CD8+ T cells by flow cytometry. PD-1 and TIM-3 expression levels were significantly higher on CD4+ T and CD8+ T cells from co-infected patients than on those from the HBV patients. In addition, CD4+ T cells and CD8+ T cells function were significantly inhibited by C. sinensis and HBV co-infection compared with HBV single infection, secreting lower levels of Interferon gamma (IFN-γ), Interleukin-2 (IL-2), and TNF-α. Our current results suggested that C. sinensis co-infection could exacerbate T cell exhaustion in patients with chronic hepatitis B. PD-1 and TIM-3 could be novel biomarkers for T cell exhaustion in patients with Clonorchis sinensis and chronic hepatitis B co-infection. Furthermore, it may be one possible reason for the weaker response to antiviral therapies and the chronicity of HBV infection in co-infected patients. We must realize the importance of C. sinensis treatment for HBV-infected patients. It might provide useful information for clinical doctors to choose the right treatment plans.
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Affiliation(s)
- Huimin Dong
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuan Liao
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Mei Shang
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yuechun Fu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hongbin Zhang
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Minqi Luo
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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15
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Gu XY, Huo JL, Yu ZY, Jiang JC, Xu YX, Zhao LJ. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects. ONCOLOGIE 2024; 26:9-25. [DOI: 10.1515/oncologie-2023-0412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Hepatocellular carcinoma (HCC) is a concerning liver cancer with rising incidence and mortality rates worldwide. The effectiveness of traditional therapies in managing advanced HCC is limited, necessitating the development of new therapeutic strategies. Immune checkpoint inhibitors (ICIs) have emerged as a promising strategy for HCC management. By preventing tumor cells from evading immune surveillance through immunological checkpoints, ICIs can restore the immune system’s ability to target and eliminate tumors. While ICIs show promise in enhancing the immune response against malignancies, challenges such as drug resistance and adverse reactions hinder their efficacy. To address these challenges, developing individualized ICI treatment strategies is critical. Combining targeted therapy and immunotherapy holds the potential for comprehensive therapeutic effects. Additionally, biomarker-based individualized ICI treatment strategies offer promise in predicting treatment response and guiding personalized patient care. Future research should explore emerging ICI treatment methods to optimize HCC immunotherapy. This review provides an overview of ICIs as a new treatment for HCC, demonstrating some success in promoting the tumor immune response. However, drug resistance and adverse reactions remain important considerations that must be addressed. As tailored treatment plans evolve, the prospect of immunotherapy for HCC is expected to grow, offering new opportunities for improved patient outcomes.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Jin-Long Huo
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Zhi-Yong Yu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ji-Chang Jiang
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Ya-Xuan Xu
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
| | - Li-Jin Zhao
- Department of General Surgery , Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University , Zunyi , China
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16
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Wilson H, Macdonald D, Bryce K. Clearance of Hepatitis C Virus following Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma: Case Report. Case Rep Gastroenterol 2024; 18:347-351. [PMID: 39015527 PMCID: PMC11250384 DOI: 10.1159/000539646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 03/19/2024] [Indexed: 07/18/2024] Open
Abstract
Introduction Patients with advanced hepatocellular carcinoma (HCC) have limited treatment options in the context of decompensated cirrhosis. HCC occurs in patients with hepatitis C virus (HCV) infection and cirrhosis at 1-4% per year. Direct-acting antiviral (DAA) efficacy is decreased in the presence of HCC. We present a case where immunotherapy may have resulted in HCV clearance, when DAA therapy had been ineffective. We hypothesise that immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway can reverse T-cell exhaustion and aid in the clearance of chronic HCV. Case Presentation This case study describes a male in his 40 s identified by a re-engagement initiative for HCV, who had been unaware of his diagnosis. On further investigation he was found to have compensated for liver cirrhosis and HCC. He was treated with HCV DAA therapy (sofosbuvir/velpatasvir) and then systemic immunotherapy for HCC with atezolizumab and bevacizumab, in an attempt to downstage the disease. Hepatitis C therapy did not achieve sustained virological response, with viral relapse after the end of treatment. This, combined with ongoing alcohol use, resulted in hepatic decompensation and cessation of immunotherapy after the fifth cycle. The HCV RNA subsequently became undetectable without further DAA re-treatment. Conclusion To our knowledge, this is the first case of HCV clearance after DAA relapse and the timing of this event after immunotherapy suggests a causal link. We hypothesise that this may be due to the reversal of antiviral T-cell exhaustion. This would therefore support further investigation into other chronic viral infections that create tumour associated with immunosuppressive microenvironments.
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Affiliation(s)
- Harry Wilson
- Hepatology Department, Royal Free Hospital, London, UK
| | | | - Kathleen Bryce
- Hepatology Department, Royal Free Hospital, London, UK
- Insitute for Global Health, University College London University, London, UK
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17
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Su M, Ye T, Wu W, Shu Z, Xia Q. Possibility of PD-1/PD-L1 Inhibitors for the Treatment of Patients with Chronic Hepatitis B Infection. Dig Dis 2023; 42:53-60. [PMID: 37820605 PMCID: PMC10836741 DOI: 10.1159/000534535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/03/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Chronic hepatitis B (CHB) infection is still a major global public health problem, with nearly two billion patients. Although current antiviral drugs can inhibit viral replication and reduce hepatitis B virus (HBV) related complications, it is difficult to achieve clinical endpoints due to drug resistance. SUMMARY Immune checkpoint inhibitors (ICIs) are an important strategy to reverse T-cell exhaustion, and rebuilding an effective functional T-cell response is a promising immunomodulatory approach for CHB patients. However, ICIs may lead to viral reactivation or immune-related adverse effects. There are still many controversies in the application of ICIs in treating patients with CHB. KEY MESSAGES This article reviews the research progress of ICIs in CHB infection and related issues. The goal of this paper was to summarize the possible impact of new therapies for CHB with the aim of reducing potential clinical risks.
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Affiliation(s)
- Menghan Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,
| | - Ting Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zheyue Shu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China
| | - Qi Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China
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18
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Nardo M, Yilmaz B, Nelson BE, Torres HA, Wang LS, Granwehr BP, Song J, Dalla Pria HRF, Trinh VA, Glitza Oliva IC, Patel SP, Tannir NM, Kaseb AO, Altan M, Lee SS, Miller E, Zhang H, Stephen BA, Naing A. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience. Oncologist 2023; 28:714-721. [PMID: 36952233 PMCID: PMC10400154 DOI: 10.1093/oncolo/oyad039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/24/2023] [Indexed: 03/24/2023] Open
Abstract
BACKGROUND Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.
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Affiliation(s)
- Mirella Nardo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bulent Yilmaz
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Blessie Elizabeth Nelson
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Harrys A Torres
- Department of Infectious Diseases Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lan Sun Wang
- Department of Genitourinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bruno Palma Granwehr
- Department of Infectious Diseases Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Juhee Song
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hanna R F Dalla Pria
- Department of Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Van A Trinh
- Department of Melanoma Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Isabella C Glitza Oliva
- Department of Melanoma Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sapna P Patel
- Department of Melanoma Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nizar M Tannir
- Department of Genitourinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed Omar Kaseb
- Department of Genitourinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mehmet Altan
- Department of Genitourinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston TX, USA
| | - Sunyoung S Lee
- Department of Gastrointestinal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ethan Miller
- Department of Gastrointestinal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hao Zhang
- Department of Gastrointestinal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bettzy A Stephen
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Zhou S, Zhao Z, Zhong H, Ren Z, Li Y, Wang H, Qiu Y. The role of myeloid-derived suppressor cells in liver cancer. Discov Oncol 2023; 14:77. [PMID: 37217620 DOI: 10.1007/s12672-023-00681-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/09/2023] [Indexed: 05/24/2023] Open
Abstract
MDSCs are immature myeloid immune cells, which accumulate in models of liver cancer to reduce effector immune cell activity, contribute to immune escape and treatment resistance. The accumulation of MDSCs suppresses the role of CTL and the killing effects of NK cells, induces the accumulation of Treg cells, and blocks the antigen presentation of DCs, thus promoting the progression of liver cancer. Recently, immunotherapy has emerged a valuable approach following chemoradiotherapy in the therapy of advanced liver cancer. A considerable increasing of researches had proved that targeting MDSCs has become one of the therapeutic targets to enhance tumor immunity. In preclinical study models, targeting MDSCs have shown encouraging results in both alone and in combination administration. In this paper, we elaborated immune microenvironment of the liver, function and regulatory mechanisms of MDSCs, and therapeutic approaches to target MDSCs. We also expect these strategies to supply new views for future immunotherapy for the treatment of liver cancer.
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Affiliation(s)
- Shiyue Zhou
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin, 301617, People's Republic of China
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Rd., West Area, Tuanbo New Town, Jinghai Dist, Tianjin, 301617, China
| | - Zixuan Zhao
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin, 301617, People's Republic of China
| | - Hao Zhong
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin, 301617, People's Republic of China
| | - Zehao Ren
- School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
| | - Yuye Li
- Binhai New Area Hospital of TCM, Tianjin, 300451, China.
| | - Hong Wang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Rd., West Area, Tuanbo New Town, Jinghai Dist, Tianjin, 301617, China.
| | - Yuling Qiu
- School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
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20
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Nikoo M, Hassan ZF, Mardasi M, Rostamnezhad E, Roozbahani F, Rahimi S, Mohammadi J. Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy. Pathol Res Pract 2023; 247:154473. [PMID: 37207558 DOI: 10.1016/j.prp.2023.154473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G. C., Evin, Tehran, Iran
| | - Elmira Rostamnezhad
- Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahel Rahimi
- Industrial and Environmental Biotechnology Department, National Institute of Genetic Engineering and Biotechnology(NIGEB), Tehran, Iran
| | - Javad Mohammadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
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21
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Puerta CJ, Cuellar A, Lasso P, Mateus J, Gonzalez JM. Trypanosoma cruzi-specific CD8 + T cells and other immunological hallmarks in chronic Chagas cardiomyopathy: Two decades of research. Front Cell Infect Microbiol 2023; 12:1075717. [PMID: 36683674 PMCID: PMC9846209 DOI: 10.3389/fcimb.2022.1075717] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/01/2022] [Indexed: 01/05/2023] Open
Abstract
Trypanosoma cruzi, the causal agent of Chagas disease, has coexisted with humans for thousands of years. Therefore, the parasite has developed several mechanisms of antigenic variability that has allowed it to live inside the cells and evade the host immune response. Since T. cruzi displays an intracellular cycle-stage, our research team focused on providing insights into the CD8+ T cells immune response in chronic Chagas cardiomyopathy. We began our work in the 2000s studying parasite antigens that induce natural immune responses such as the KMP11 protein and TcTLE, its N-terminal derived peptide. Different approaches allowed us to reveal TcTLE peptide as a promiscuous CD8+ T cell epitope, able of inducing multifunctional cellular immune responses and eliciting a humoral response capable of decreasing parasite movement and infective capacity. Next, we demonstrated that as the disease progresses, total CD8+ T cells display a dysfunctional state characterized by a prolonged hyper-activation state along with an increase of inhibitory receptors (2B4, CD160, PD-1, TIM-3, CTLA-4) expression, an increase of specific terminal effector T cells (TTE), a decrease of proliferative capacity, a decrease of stem cell memory (TSCM) frequency, and a decrease of CD28 and CD3ζ expression. Thus, parasite-specific CD8+ T cells undergo clonal exhaustion, distinguished by an increase in late-differentiated cells, a mono-functional response, and enhanced expression of inhibitory receptors. Finally, it was found that anti-parasitic treatment induces an improved CD8+ T cell response in asymptomatic individuals, and a mouse animal model led us to establish a correlation between the quality of the CD8+ T cell responses and the outcome of chronic infection. In the future, using OMICs strategies, the identification of the specific cellular signals involved in disease progression will provide an invaluable resource for discovering new biomarkers of progression or new vaccine and immunotherapy strategies. Also, the inclusion of the TcTLE peptide in the rational design of epitope-based vaccines, the development of immunotherapy strategies using TSCM or the blocking of inhibitory receptors, and the use of the CD8+ T cell response quality to follow treatments, immunotherapies or vaccines, all are alternatives than could be explored in the fight against Chagas disease.
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Affiliation(s)
- Concepción J. Puerta
- Laboratory of Molecular Parasitology, Infectious Diseases Group, Department of Microbiology, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Adriana Cuellar
- Clinical Laboratory Sciences Group, Department of Microbiology, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Paola Lasso
- Laboratory of Molecular Parasitology, Infectious Diseases Group, Department of Microbiology, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Jose Mateus
- Laboratory of Molecular Parasitology, Infectious Diseases Group, Department of Microbiology, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - John M. Gonzalez
- Group of Biomedical Sciences, School of Medicine, Universidad de Los Andes, Bogotá, Colombia
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22
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Darmadi D, Lindarto D, Siregar J, Widyawati T, Rusda M, Amin MM, Yusuf F, Eyanoer PC, Lubis M, Rey I. Study of the Molecular Dynamics Stability in the Inhibitory Interaction of Tenofovir Disoproxil Fumarate against CTLA-4 in Chronic Hepatitis B Patients. Med Arch 2023; 77:227-230. [PMID: 37700917 PMCID: PMC10495148 DOI: 10.5455/medarh.2023.77.227-230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/24/2023] [Indexed: 09/14/2023] Open
Abstract
Background Tenofovir disoproxil fumarate (TDF) is a first-line nucleotide analog (NA) drug for hepatitis B therapy. Long-term NA therapy increases peripheral T cell levels to enhance antiviral response, while CTLA-4 inhibits the activation. Objective This study analyzed the interaction between TDF and CTLA-4 through molecular docking. Methods Target protein and ligand data mining were performed, and proteins were prepared by removing water molecules in the Discovery Studio 2019 software. The energy minimization was performed on ligands using Pyrx v.0.9.8 software. Protein-ligand docking was performed using Autodock Vina integrated with Pyrx v.09.8. Meanwhile, the docking of proteins was accomplished using the Haddock server. The BioVia Discovery Studio 2019 software visualized the interaction between the compound and the docked protein. Molecular dynamics simulations were carried out using the YASARA Dynamic program developed by Biosciences GmbH. Results TDF ligand has good and stable inhibitory activity against the CTLA-4/B7-1 and CTLA4/B7-2 complexes. TDF docking has been shown to initiate conformational changes, indicating the ligand's inhibitory activity. The significant conformational changes based on superimposition results were shown by the CTLA-4/TDF/B7-2 and CTLA-4/B7-1/TDF complexes. TDF in all ligands undergoes bonding and displacement of binding sites. Conclusion Treatment with TDF was predicted to have inhibitory activity against CTLA-4, especially in its complex form with B7-1 and B7-2.
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Affiliation(s)
- Darmadi Darmadi
- Philosophy Doctor in Medicine Program, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Dharma Lindarto
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Jelita Siregar
- Department of Clinical Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Tri Widyawati
- Department of Pharmacology and Therapeutic, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- Master Program in Tropical Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Muhammad Rusda
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Mustafa Mahmud Amin
- Department of Psychiatry, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Fauzi Yusuf
- Department of Internal Medicine, Faculty of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
| | - Putri Chairani Eyanoer
- Department of Public Health, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Imelda Rey
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
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24
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Corkum CP, Wiede LL, Ruble CLA, Qiu J, Mulrooney-Cousins PM, Steeves MA, Watson DE, Michalak TI. Identification of antibodies cross-reactive with woodchuck immune cells and activation of virus-specific and global cytotoxic T cell responses by anti-PD-1 and anti-PD-L1 in experimental chronic hepatitis B and persistent occult hepadnaviral infection. Front Microbiol 2022; 13:1011070. [PMID: 36560951 PMCID: PMC9764628 DOI: 10.3389/fmicb.2022.1011070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022] Open
Abstract
Woodchuck (Marmota monax) infected with woodchuck hepatitis virus (WHV) is the most pathogenically compatible naturally occurring model of human hepatitis B virus (HBV) infection, chronic hepatitis B, and HBV-induced hepatocellular carcinoma. This system plays a crucial role in discovery and preclinical evaluation of anti-HBV therapies. Its utilization remains tempered by the relatively narrow range of validated immunologic and molecular tools. We evaluated commercial antibodies against immune cell phenotypic markers and T cell molecules for cross-reactivity with woodchuck antigenic equivalents. The confirmed antibodies against programed cell death protein-1 (PD-1) and its ligand (PD-L1) were examined for ex vivo ability to activate WHV-specific, global and bystander cytotoxic T cells (CTLs) in chronic hepatitis and asymptomatic infection persisting after self-resolved acute hepatitis. Examination of 65 antibodies led to identification or confirmation of 23 recognizing woodchuck T, regulatory T, B and natural killer cells, T cell-associated PD-1, PD-L1, CTLA-4 and TIM-3 molecules, CD25 and CD69 markers of T cell activation, and interferon gamma (IFNγ). Antibodies against woodchuck PD-1 and PD-L1 triggered in vitro highly individualized WHV-specific and global activation of CTLs in both chronic hepatitis and persistent occult infection. WHV-specific CTLs were more robustly augmented by anti-PD-1 than by anti-PD-L1 in chronic hepatitis, while global IFNγ-positive CTL response was significantly suppressed in chronic hepatitis compared to persistent occult infection. Anti-PD-1 and anti-PD-L1 also occasionally activated CTLs to specificities other than those tested suggesting their potency to trigger side effects. This was particularly apparent when T cells from chronic hepatitis were treated with anti-PD-L1. The current findings indicate that inhibition of the PD-1/PD-L1 pathway could reactivate virus-specific and global T cell responses in both chronic hepatitis and asymptomatic persistent infection. They suggest a mechanism of potential reactivation of clinically silent infection during anti-PD-1/PD-L1 treatment and indicate that this therapy may also subdue occult HBV infection.
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Affiliation(s)
- Christopher P. Corkum
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Louisa L. Wiede
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Cara L.-A. Ruble
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Jiabin Qiu
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Patricia M. Mulrooney-Cousins
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Meredith A. Steeves
- Non-Clinical Safety Assessment, Toxicology, Elli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, United States
| | - David E. Watson
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Tomasz I. Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada,*Correspondence: Tomasz I. Michalak,
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25
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Nicholas B, Lee HH, Guo J, Cicmil M, Blume C, Malefyt RDW, Djukanović R. Immunomodulatory regulator blockade in a viral exacerbation model of severe asthma. Front Immunol 2022; 13:973673. [PMID: 36479132 PMCID: PMC9720166 DOI: 10.3389/fimmu.2022.973673] [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: 06/21/2022] [Accepted: 11/03/2022] [Indexed: 11/22/2022] Open
Abstract
Asthmatics are more susceptible to viral infections than healthy individuals and are known to have impaired innate anti-viral defences. Influenza A virus causes significant morbidity and mortality in this population. Immuno-modulatory regulators (IMRs) such as PD-1 are activated on T cells following viral infection as part of normal T cell activation responses, and then subside, but remain elevated in cases of chronic exposure to virus, indicative of T cell exhaustion rather than activation. There is evidence that checkpoint inhibition can enhance anti-viral responses during acute exposure to virus through enhancement of CD8+T cell function. Although elevated PD-1 expression has been described in pulmonary tissues in other chronic lung diseases, the role of IMRs in asthma has been relatively unexplored as the basis for immune dysfunction. We first assessed IMR expression in the peripheral circulation and then quantified changes in IMR expression in lung tissue in response to ex-vivo influenza infection. We found that the PD-1 family members are not significantly altered in the peripheral circulation in individuals with severe asthma but are elevated in pulmonary tissues following ex-vivo influenza infection. We then applied PD-1 Mab inhibitor treatment to bronchial biopsy tissues infected with influenza virus and found that PD-1 inhibition was ineffective in asthmatics, but actually increased infection rates in healthy controls. This study, therefore, suggests that PD-1 therapy would not produce harmful side-effects when applied in people with severe asthma, but could have important, as yet undescribed, negative effects on anti-viral responses in healthy individuals that warrant further investigation.
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Affiliation(s)
- Ben Nicholas
- Division of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Hampshire, United Kingdom,*Correspondence: Ben Nicholas,
| | - Hyun-Hee Lee
- Oncology & Immunology Discovery, Merck Research Laboratories, Boston, MA, United States
| | - Jane Guo
- Oncology & Immunology Discovery, Merck Research Laboratories, Boston, MA, United States
| | - Milenko Cicmil
- Oncology & Immunology Discovery, Merck Research Laboratories, Boston, MA, United States
| | - Cornelia Blume
- Division of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Hampshire, United Kingdom
| | | | - Ratko Djukanović
- Division of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital, Hampshire, United Kingdom
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26
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Prostaglandin E 2-Induced Immune Suppression via Cytotoxic T-Lymphocyte Antigen 4 in Paratuberculosis. Infect Immun 2022; 90:e0021022. [PMID: 36102658 PMCID: PMC9584316 DOI: 10.1128/iai.00210-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Paratuberculosis is a chronic enteritis of ruminants caused by the facultative intracellular pathogen Mycobacterium avium subsp. paratuberculosis. The Th1 response inhibits the proliferation of M. avium subsp. paratuberculosis during the early subclinical stage. However, we have previously shown that immune inhibitory molecules, such as prostaglandin E2 (PGE2), suppress M. avium subsp. paratuberculosis-specific Th1 responses as the disease progresses. To date, the mechanism underlying immunosuppression during M. avium subsp. paratuberculosis infection has not been elucidated. Therefore, in the present study, we investigated the function of cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed by peripheral blood mononuclear cells (PBMCs) from cattle with paratuberculosis because CTLA-4 expression is known to be elevated in T cells under an M. avium subsp. paratuberculosis experimental infection. M. avium subsp. paratuberculosis antigen induced CTLA-4 expression in T cells from cattle experimentally infected with M. avium subsp. paratuberculosis. Interestingly, both PGE2 and an E prostanoid 4 agonist also induced CTLA-4 expression in T cells. In addition, a functional assay with a bovine CTLA-4-immunogobulin fusion protein (CTLA-4-Ig) indicated that CTLA-4 inhibited gamma interferon (IFN-γ) production in M. avium subsp. paratuberculosis-stimulated PBMCs, while blockade by anti-bovine CTLA-4 monoclonal antibody increased the secretion of IFN-γ and tumor necrosis factor alpha production in these PBMCs. These preliminary findings show that PGE2 has immunosuppressive effects via CTLA-4 to M. avium subsp. paratuberculosis. Therefore, it is necessary to clarify in the future whether CTLA-4-mediated immunosuppression facilitates disease progression of paratuberculosis in cattle.
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27
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Nishio A, Hasan S, Park H, Park N, Salas JH, Salinas E, Kardava L, Juneau P, Frumento N, Massaccesi G, Moir S, Bailey JR, Grakoui A, Ghany MG, Rehermann B. Serum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C. Nat Commun 2022; 13:5446. [PMID: 36114169 PMCID: PMC9481596 DOI: 10.1038/s41467-022-33035-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection.
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Affiliation(s)
- Akira Nishio
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Sharika Hasan
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Heiyoung Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Nana Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Jordan H Salas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Eduardo Salinas
- Division of Infectious Diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory National Primate Research Center, Emory Vaccine Center, Atlanta, GA, 30329, USA
| | - Lela Kardava
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Paul Juneau
- Division of Data Services, NIH Library, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
- Contractor- Zimmerman Associates, Inc, Fairfax, VA, USA
| | - Nicole Frumento
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Guido Massaccesi
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Susan Moir
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Justin R Bailey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Arash Grakoui
- Division of Infectious Diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory National Primate Research Center, Emory Vaccine Center, Atlanta, GA, 30329, USA
| | - Marc G Ghany
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA.
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Tada T, Norton TD, Leibowitz R, Landau NR. Directly injected lentiviral vector-based T cell vaccine protects mice against acute and chronic viral infection. JCI Insight 2022; 7:161598. [PMID: 35972807 PMCID: PMC9675446 DOI: 10.1172/jci.insight.161598] [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: 05/03/2022] [Accepted: 08/11/2022] [Indexed: 12/01/2022] Open
Abstract
Lentiviral vector–based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen-expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I–restricted T cell epitope of lymphocytic choriomeningitis virus (LCMV) and CD40 ligand induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble programmed cell death 1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in sterile alpha motif and HD-domain containing protein 1–knockout (SAMHD1-knockout) mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.
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Affiliation(s)
- Takuya Tada
- Department of Medicine, NYU Grossman School of Medicine, New York, United States of America
| | - Thomas D Norton
- Department of Medicine, NYU Grossman School of Medicine, New York, United States of America
| | - Rebecca Leibowitz
- Department of Microbiology, NYU Grossman School of Medicine, New York, United States of America
| | - Nathaniel R Landau
- Department of Microbiology, NYU Grossman School of Medicine, New York, United States of America
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Li S, Li N, Yang S, Deng H, Li Y, Wang Y, Yang J, Lv J, Dong L, Yu G, Hou X, Wang G. The study of immune checkpoint inhibitors in chronic hepatitis B virus infection. Int Immunopharmacol 2022; 109:108842. [DOI: 10.1016/j.intimp.2022.108842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/19/2022] [Accepted: 05/04/2022] [Indexed: 11/09/2022]
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Viramontes KM, Neubert EN, DeRogatis JM, Tinoco R. PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells. Front Immunol 2022; 13:869768. [PMID: 35774790 PMCID: PMC9237324 DOI: 10.3389/fimmu.2022.869768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 05/23/2022] [Indexed: 11/25/2022] Open
Abstract
Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 (Selplg) are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs). While PSGL-1 has been shown to inhibit T cell responses in various disease models, the cell-intrinsic function of PSGL-1 in the differentiation, maintenance, and reinvigoration of exhausted T cells is unknown. We found Selplg-/- T cells had increased expansion in melanoma tumors and in early stages of chronic viral infection. Despite their increase, both WT and Selplg-/- T cells eventually became phenotypically and functionally exhausted. Even though virus-specific Selplg-/- CD4+ and CD8+ T cells were increased at the peak of T cell expansion, they decreased to lower levels than WT T cells at later stages of chronic infection. We found that Selplg-/- CD8+ Tpex (SLAMF6hiTIM3lo, PD-1+TIM3+, TOX+, TCF-1+) cell frequencies and numbers were decreased compared to WT T cells. Importantly, even though virus-specific Selplg-/- CD4+ and CD8+ T cells were lower, they were reinvigorated more effectively than WT T cells after anti-PD-L1 treatment. We found increased SELPLG expression in Hepatitis C-specific CD8+ T cells in patients with chronic infection, whereas these levels were decreased in patients that resolved the infection. Together, our findings showed multiple PSGL-1 regulatory functions in exhausted T cells. We found that PSGL-1 is a cell-intrinsic inhibitor that limits T cells in tumors and in persistently infected hosts. Additionally, while PSGL-1 is linked with T cell exhaustion, its expression was required for their long-term maintenance and optimal differentiation into Tpex cells. Finally, PSGL-1 restrained the reinvigoration potential of exhausted CD4+ and CD8+ T cells during ICI therapy. Our findings highlight that targeting PSGL-1 may have therapeutic potential alone or in combination with other ICIs to reinvigorate exhausted T cells in patients with chronic infections or cancer.
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Affiliation(s)
- Karla M. Viramontes
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, CA, United States
| | - Emily N. Neubert
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, CA, United States
- Center for Virus Research, University of California, Irvine, Irvine, CA, United States
| | - Julia M. DeRogatis
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, CA, United States
| | - Roberto Tinoco
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, CA, United States
- Center for Virus Research, University of California, Irvine, Irvine, CA, United States
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Saber MM. Diagnostic Performance of PD-L1 versus PD-1 Expression in Circulating CD20 Cells in Diffuse Large B-Cell Lymphoma. Antibodies (Basel) 2022; 11:antib11010015. [PMID: 35225873 PMCID: PMC8884023 DOI: 10.3390/antib11010015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/16/2022] Open
Abstract
This study aimed to investigate PD-L1 and PD-1 expression in circulating CD20+ cells in diffuse larger B-cell lymphoma (DLBCL) and to evaluate the predictive and diagnostic performance of PD-L1 versus PD-1 expression in circulating CD20+ cells in DLBCL. Percentages of CD20+, PD-L1+CD20+, and PD-1+CD20+ cells were measured by flow cytometry in 40 DLBCL blood samples and 19 healthy controls. The DLBCL patient group was subdivided into 20 newly diagnosed patients with no treatment yet and 20 patients that had finished six cycles of CHOP therapy. Percentages of PD-L1+CD20+ and PD-1+CD20+ cells were highly significantly increased in pre-therapy patients in comparison to healthy volunteers (p < 0.001). Meanwhile, a significant decrease in percentages of PD-L1+CD20+ and PD-1+CD20+ was observed in post-CHOP therapy patients in comparison to pre-therapy patients (p < 0.001). PD-L1+CD20+ cells were significantly decreased in post-therapy patients when compared to normal controls (p < 0.001), while not for PD-1+CD20+ cells. A strong significant positive correlation between percentages of PD-L1+CD20+ and PD-1+CD20+ was detected in DLBCL patients (p < 0.001). In the pre-therapy group, high PD-L1+CD20+ and PD-1+CD20+ percentages were correlated with serum LDH levels (p = 0.021, p < 0.001). High percentages of PD-1+CD20+ were found in DLBCL patients with splenomegaly (p = 0.027). The results revealed that patients with advanced tumor stages, poor ECOG performance, and non-GCB DLBCL type had increased percentages of PD-L1+CD20+ and PD-1+CD20+ cells. Moreover, PD-L1+CD20+ % and PD-1+CD20+ % were significantly increased in DLBCL patients with bone marrow involvement or B symptoms. The superiority of PD-L1+CD20+ over PD-1+CD20+ was more profound in DLBCL prediction [AUC: 1.0] and in discriminating newly diagnosed patients [AUC: 1.0]. The findings suggest that increased PD-L1/PD-1 expression in peripheral CD20 cells may serve as a companion diagnostic marker for DLBCL. Moreover, percentages of PD-L1+CD20+ cells have better diagnostic performance with higher sensitivity and specificity than PD-1+CD20+ %.
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Affiliation(s)
- Manal Mohamed Saber
- Clinical Pathology Department, Faculty of Medicine, Minia University, Minia 61519, Egypt
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32
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Lee JC, Green MD, Huppert LA, Chow C, Pierce RH, Daud AI. The Liver-Immunity Nexus and Cancer Immunotherapy. Clin Cancer Res 2022; 28:5-12. [PMID: 34285059 PMCID: PMC8897983 DOI: 10.1158/1078-0432.ccr-21-1193] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/24/2021] [Accepted: 07/16/2021] [Indexed: 01/03/2023]
Abstract
The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.
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Affiliation(s)
- James C. Lee
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco,
California
| | - Michael D. Green
- Department of Radiation Oncology, Michigan Medicine,
University of Michigan, Ann Arbor, Michigan.,Veterans Affairs Ann Arbor Healthcare System, U.S.
Department of Veterans Affairs, Ann Arbor, Michigan
| | - Laura A. Huppert
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California
| | - Christine Chow
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California
| | | | - Adil I. Daud
- Divisions of Hematology and Medical Oncology, Department of
Medicine, University of California San Francisco, San Francisco, California.,Parker Institute for Cancer Immunotherapy, San Francisco,
California
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33
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Zhong L, Zhong P, Liu H, Li Z, Nie Q, Peng W. Hepatitis B virus infection does not affect the clinical outcome of anti-programmed death receptor-1 therapy in advanced solid malignancies: Real-world evidence from a retrospective study using propensity score matching. Medicine (Baltimore) 2021; 100:e28113. [PMID: 34889269 PMCID: PMC8663830 DOI: 10.1097/md.0000000000028113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 11/16/2021] [Indexed: 01/05/2023] Open
Abstract
This study aimed to investigate the impact of hepatitis B virus (HBV) infection on the outcome of patients with advanced solid malignancies treated with programmed death receptor-1 (PD-1) inhibitors.We retrospectively included patients treated with PD-1 inhibitors between August 2018 and April 2020. Propensity score matching (PSM) was performed to match the characteristics of the HBV and non-HBV groups. Objective response rate (ORR) and disease control rate (DCR) were compared between HBV and non-HBV groups using χ2 or Fisher exact tests. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) and progression-free survival (PFS).A total of 120 patients, including 43 (35.8%) with HBV and 77 (64.2%) without HBV, were enrolled. Cases of HBV reactivation were not observed. In the entire study population, ORR and DCR did not significantly differ between both groups. After PSM, the study population comprised 39 patients, 15 with and 24 without HBV. The HBV group had an ORR of 55.6%, whereas the ORR in the non-HBV group was 36.8% (P = .35). Similarly, the DCR was 77.8% in the HBV group, as compared to 68.4% in the non-HBV group (P = .61). Additionally, HBV infection did not significantly affect OS (P = .54) and PFS (P = .64) in the unmatched cohort. Moreover, statistically significant differences regarding OS (P = .15) and PFS (P = .23) were also not detected after PSM.In conclusion, the HBV infection status did not impact the therapy response or prognosis of patients treated with PD-1 inhibitors. Further prospective studies are needed to corroborate these findings.
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Affiliation(s)
- Liting Zhong
- Department of Oncology, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
| | - PinShun Zhong
- Department of Respiratory Medicine, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
| | - Huafeng Liu
- Department of Oncology, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
| | - Zelei Li
- Department of Oncology, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
| | - Qihong Nie
- Department of Oncology, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
| | - Weiwei Peng
- Department of Oncology, Ganzhou People's Hospital (The Affiliated Ganzhou Hospital of Nanchang University), Ganzhou, Jiangxi, China
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Watari K, Konnai S, Okagawa T, Maekawa N, Sajiki Y, Kato Y, Suzuki Y, Murata S, Ohashi K. Enhancement of interleukin-2 production by bovine peripheral blood mononuclear cells treated with the combination of anti-programmed death-ligand 1 and cytotoxic T lymphocyte antigen 4 chimeric monoclonal antibodies. J Vet Med Sci 2021; 84:6-15. [PMID: 34789592 PMCID: PMC8810316 DOI: 10.1292/jvms.21-0552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Our previous studies demonstrate the therapeutic efficacy against bovine diseases of an anti-bovine programmed death-ligand 1 (PD-L1) chimeric antibody. In humans, PD-1 and PD-L1 antibodies are more effective when combined with an antibody targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and these combination therapies are therefore clinically used. Here we generated an anti-bovine CTLA-4 chimeric antibody (chAb) to enhance the therapeutic efficacy of the PD-L1 antibody. We further analyzed the effects of dual blockade of CTLA-4 and PD-1 pathways on T-cell responses. The established anti-bovine CTLA-4 chAb showed comparable blocking activity on the binding of bovine CTLA-4 to CD80 and CD86 as the anti-bovine CTLA-4 mouse monoclonal antibody. Anti-bovine CTLA-4 chAb also significantly increased IL-2 production from bovine peripheral blood mononuclear cells (PBMCs). Further, the combination of anti-CTLA-4 chAb with anti-PD-L1 chAb significantly upregulated IL-2 production by PBMCs. These results suggest that the combination of antibodies have higher potential to enhance immune responses against pathogens compared with single administration.
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Affiliation(s)
- Kei Watari
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University
| | - Satoru Konnai
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Tomohiro Okagawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Naoya Maekawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Yamato Sajiki
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine
| | - Yasuhiko Suzuki
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University.,Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University.,Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University
| | - Shiro Murata
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Kazuhiko Ohashi
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
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Zhu J, Tang B, Gao Y, Xu S, Tu J, Wang Y, Yang W, Fang S, Weng Q, Zhao Z, Xu M, Yang Y, Chen M, Lu C, Ji J. Predictive Models for HCC Prognosis, Recurrence Risk, and Immune Infiltration Based on Two Exosomal Genes: MYL6B and THOC2. J Inflamm Res 2021; 14:4089-4109. [PMID: 34466015 PMCID: PMC8403029 DOI: 10.2147/jir.s315957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC. Objective The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis. Methods Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2. Results The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P<0.001), the ICGC cohort (HR=3.15, P<0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P<0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P<0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules. Conclusion Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.
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Affiliation(s)
- Jinyu Zhu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
| | - Bufu Tang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People's Republic of China
| | - Yang Gao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Suqin Xu
- Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People's Republic of China
| | - Jianfei Tu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yajie Wang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Weibin Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Shiji Fang
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Qiaoyou Weng
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Zhongwei Zhao
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Min Xu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Yang Yang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Minjiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Chenying Lu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
| | - Jiansong Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People's Republic of China.,Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People's Republic of China
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Montella L, Sarno F, Ambrosino A, Facchini S, D’Antò M, Laterza MM, Fasano M, Quarata E, Ranucci RAN, Altucci L, Berretta M, Facchini G. The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma. Cells 2021; 10:1909. [PMID: 34440678 PMCID: PMC8393830 DOI: 10.3390/cells10081909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.
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Affiliation(s)
- Liliana Montella
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Federica Sarno
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Annamaria Ambrosino
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Sergio Facchini
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Maria D’Antò
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Maria Maddalena Laterza
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Morena Fasano
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Ermelinda Quarata
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Raffaele Angelo Nicola Ranucci
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Lucia Altucci
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Gaetano Facchini
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
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Dolina JS, Van Braeckel-Budimir N, Thomas GD, Salek-Ardakani S. CD8 + T Cell Exhaustion in Cancer. Front Immunol 2021; 12:715234. [PMID: 34354714 PMCID: PMC8330547 DOI: 10.3389/fimmu.2021.715234] [Citation(s) in RCA: 278] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/02/2021] [Indexed: 12/11/2022] Open
Abstract
A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.
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Affiliation(s)
- Joseph S Dolina
- Cancer Immunology Discovery, Pfizer, San Diego, CA, United States
| | | | - Graham D Thomas
- Cancer Immunology Discovery, Pfizer, San Diego, CA, United States
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Ahdoot M, Theodorescu D. Immunotherapy of high risk non-muscle invasive bladder cancer. Expert Rev Clin Pharmacol 2021; 14:1345-1352. [PMID: 34187272 DOI: 10.1080/17512433.2021.1950531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Bladder cancer remains a prevalent and often lethal cancer. Fortunately, recent clinical trials using immunotherapeutics demonstrate promise to improve treatment outcomes. Several of these immunotherapies have already established their value in the metastatic space and likely will soon have indications in the non-metastatic space. AREAS COVERED This review will cover immunotherapies ranging for well-studied BCG administration to more novel medications such as PD-L1/PD-1 inhibitors, CTLA-4 inhibitors, IL-15 super agonists, and immune modulating gene therapies. Specifically, the article will address the mechanisms of actions, clinical evidence supporting their use, and the presence of any FDA regulatory approval for these medications in the treatment of high-risk non-muscle invasive bladder cancer. EXPERT OPINION With the publication of clinical data supporting the use of immunotherapies, these novel medications are likely to be adopted for treatment of high grade non-metastatic bladder cancer. While BCG is likely to remain a primary medication for high grade bladder cancer for the near future, BCG will likely be co-administered with immunomodulatory medications in some patients to enhance the medications effect in the future. Clinical trials are still ongoing and will demonstrate which of these multiple treatment options yield results worthy of a modification in our current treatment paradigm.
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Affiliation(s)
- Michael Ahdoot
- Department of Surgery (Urology), Cedars-Sinai Medical Center, 8700 Beverly Blvd: Los Angeles CA 90048, Los Angeles, CA, USA.,Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd: Los Angeles CA 90048, USA
| | - Dan Theodorescu
- Department of Surgery (Urology), Cedars-Sinai Medical Center, 8700 Beverly Blvd: Los Angeles CA 90048, Los Angeles, CA, USA.,Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd: Los Angeles CA 90048, USA.,Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd: Los Angeles CA 90048, USA
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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40
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Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells. Sci Rep 2021; 11:9561. [PMID: 33953256 PMCID: PMC8100288 DOI: 10.1038/s41598-021-88965-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 04/07/2021] [Indexed: 01/29/2023] Open
Abstract
Extracellular adenosine suppresses T cell immunity in the tumor microenvironment and in vitro treatment of memory T cells with adenosine can suppress antigen-mediated memory T cell expansion. We describe utilizing the recall antigen assay platform to screen small molecule drug off-target effects on memory T cell expansion/function using a dosing regimen based on adenosine treatment. As a proof of principle, we show low dose GS-5734, a monophosphoramidate prodrug of an adenosine analog, does not alter memory T cell recall at lower doses whereas toxicity observed at high dose favors antigen-specific memory T cell survival/proliferation over non-specific CD8+ T cells. Conversely, parent nucleoside GS-441524 at high dosage does not result in cellular toxicity and reduces antigen-specific T cell recall in most donors. Despite similar chemical structure, these drugs displayed opposing effects on memory T cell expansion and viability highlighting the sensitivity of this assay setup in screening compounds for off-target effects.
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Peña-Asensio J, Calvo H, Torralba M, Miquel J, Sanz-de-Villalobos E, Larrubia JR. Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8 + T Cell Response during Chronic Hepatitis C. Cells 2021; 10:cells10030538. [PMID: 33802622 PMCID: PMC8001543 DOI: 10.3390/cells10030538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.
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MESH Headings
- Antibodies, Monoclonal/therapeutic use
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/genetics
- B7-H1 Antigen/immunology
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/virology
- Gene Expression Regulation
- Hepacivirus/immunology
- Hepacivirus/pathogenicity
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions/drug effects
- Host-Pathogen Interactions/genetics
- Host-Pathogen Interactions/immunology
- Humans
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Cellular/drug effects
- Immunotherapy/methods
- Interleukins/genetics
- Interleukins/immunology
- Interleukins/therapeutic use
- Lymphocyte Activation/drug effects
- Precursor Cells, T-Lymphoid/drug effects
- Precursor Cells, T-Lymphoid/immunology
- Precursor Cells, T-Lymphoid/virology
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- Receptors, Antigen, T-Cell, gamma-delta/agonists
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Signal Transduction
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Affiliation(s)
- Julia Peña-Asensio
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Department of Biology of Systems, University of Alcalá, E-28805 Alcalá de Henares, Spain
| | - Henar Calvo
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Miguel Torralba
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Service of Internal Medicine, Guadalajara University Hospital, E-19002 Guadalajara, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, E-28805 Alcalá de Henares, Spain
| | - Joaquín Miquel
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Eduardo Sanz-de-Villalobos
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Juan-Ramón Larrubia
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, E-28805 Alcalá de Henares, Spain
- Correspondence: ; Tel.: +34-949-20-9200
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Zullo L, Rossi G, Dellepiane C, Tagliamento M, Alama A, Coco S, Longo L, Pronzato P, Maria AD, Genova C. Safety and efficacy of immune checkpoint inhibitors in non-small-cell lung cancer: focus on challenging populations. Immunotherapy 2021; 13:509-525. [PMID: 33626932 DOI: 10.2217/imt-2020-0226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In recent years, immune-checkpoint inhibitors (ICIs) have represented one of the major breakthroughs in advanced non-small cell lung cancer treatment scenario. However, enrollment in registering clinical trials is usually restricted, since frail patients (i.e., elderly, individuals with poor performance status and/or active brain metastases), as well as patients with chronic infections or who take concurrent medications, such as steroids, are routinely excluded. Thus, safety and efficacy of ICIs for these subgroups have not been adequately assessed in clinical trials, although these populations often occur in clinical practice. We reviewed the available data regarding the use of ICIs in these 'special' populations, including a focus on the issues raised by the administration of immunotherapy in lung cancer patients infected with Sars-Cov-2.
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Affiliation(s)
- Lodovica Zullo
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Giovanni Rossi
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy.,Department of Medical, Surgical & Experimental Sciences, Università degli Studi di Sassari, 07100 Sassari, Italy
| | - Chiara Dellepiane
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Marco Tagliamento
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Angela Alama
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Simona Coco
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Luca Longo
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Paolo Pronzato
- UO Oncologia Medica 2; IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Andrea De Maria
- UO Clinica di Malattie Infettive e Tropicali; IRCCS Ospedale Policlinico San Martino, 16100 Genova, Italy.,Dipartimento di Scienze della Salute (DISSAL), Università degli Studi di Genova, 16100 Genova, Italy
| | - Carlo Genova
- UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, 16100 Genova, Italy.,Dipartimento di Medicina Interna e Specialità Mediche (DiMI), Università degli Studi di Genova, 16100 Genova, Italy
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43
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Mahnke YD, Devevre E, Baumgaertner P, Matter M, Rufer N, Romero P, Speiser DE. Human melanoma-specific CD8(+) T-cells from metastases are capable of antigen-specific degranulation and cytolysis directly ex vivo. Oncoimmunology 2021; 1:467-530. [PMID: 22754765 PMCID: PMC3382891 DOI: 10.4161/onci.19856] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The relatively low frequencies of tumor Ag-specific T-cells in PBMC and metastases from cancer patients have long precluded the analysis of their direct ex vivo cytolytic capacity. Using a new composite technique that works well with low cell numbers, we aimed at determining the functional competence of melanoma-specific CD8+ T-cells. A multiparameter flow cytometry based technique was applied to assess the cytolytic function, degranulation and IFNγ production by tumor Ag-specific CD8+ T-cells from PBMC and tumor-infiltrated lymph nodes (TILN) of melanoma patients. We found strong cytotoxicity by T-cells not only when they were isolated from PBMC but also from TILN. Cytotoxicity was observed against peptide-pulsed target cells and melanoma cells presenting the naturally processed endogenous antigen. However, unlike their PBMC-derived counterparts, T-cells from TILN produced only minimal amounts of IFNγ, while exhibiting similar levels of degranulation, revealing a critical functional dichotomy in metastatic lesions. Our finding of partial functional impairment fits well with the current knowledge that T-cells from cancer metastases are so-called exhausted, a state of T-cell hyporesponsiveness also found in chronic viral infections. The identification of responsible mechanisms in the tumor microenvironment is important for improving cancer therapies.
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Affiliation(s)
- Yolanda D Mahnke
- Ludwig Center for Cancer Research; University of Lausanne; Lausanne, Switzerland
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Park BJ, Ahn HS, Han SH, Go HJ, Kim DH, Choi C, Jung S, Myoung J, Lee JB, Park SY, Song CS, Lee SW, Lee HT, Choi IS. Analysis of the Immune Responses in the Ileum of Gnotobiotic Pigs Infected with the Recombinant GII.p12_GII.3 Human Norovirus by mRNA Sequencing. Viruses 2021; 13:v13010092. [PMID: 33440894 PMCID: PMC7826840 DOI: 10.3390/v13010092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/29/2020] [Accepted: 01/08/2021] [Indexed: 11/20/2022] Open
Abstract
Norovirus genogroup II (NoV GII) induces acute gastrointestinal food-borne illness in humans. Because gnotobiotic pigs can be infected with human norovirus (HuNoV) GII, they are frequently used to analyze the associated pathogenic mechanisms and immune responses, which remain poorly understood. Recently, mRNA sequencing analysis (RNA-Seq) has been used to identify cellular responses to viruses. In this study, we investigated the host immune response and possible mechanisms involved in virus evasion in the ileum of gnotobiotic pigs infected with HuNoV by RNA-Seq. HuNoV was detected in the feces, blood, and tissues of the jejunum, ileum, colon, mesenteric lymph node, and spleen of pigs infected with HuNoV. In analysis of mRNA sequencing, expression of anti-viral protein genes such as OAS1, MX1, and MX2 were largely decreased, whereas type I IFN was increased in pigs infected with HuNoV. In addition, expression of TNF and associated anti-inflammatory cytokine genes such as IL10 was increased in HuNoV-infected pigs. Expression of genes related to natural killer (NK) cell cytotoxicity and CD8+ T cell exhaustion was increased, whereas that of MHC class I genes was decreased. Expression profiles of selected genes were further confirmed by qRT-PCR and Western blot. These results suggest that infection with HuNoV induces NK cell-mediated cytotoxicity but suppresses type I IFN- and CD8+ T cell-mediated antiviral responses.
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Affiliation(s)
- Byung-Joo Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Hee-Seop Ahn
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Sang-Hoon Han
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Hyeon-Jeong Go
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Dong-Hwi Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Changsun Choi
- Department of Food and Nutrition, College of Biotechnology and Natural Resources, Chung-Ang University, Anseong, Gyeonggi 17546, Korea; (C.C.); (S.J.)
| | - Soontag Jung
- Department of Food and Nutrition, College of Biotechnology and Natural Resources, Chung-Ang University, Anseong, Gyeonggi 17546, Korea; (C.C.); (S.J.)
| | - Jinjong Myoung
- Korea Zoonosis Research Institute, Chonbuk National University, Jeonju, Jeollabuk-do 54896, Korea;
| | - Joong-Bok Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Seung-Yong Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Chang-Seon Song
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Sang-Won Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Hoon-Taek Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea;
| | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea; (B.-J.P.); (H.-S.A.); (S.-H.H.); (H.-J.G.); (D.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
- Correspondence: ; Tel.: +82-2049-6228
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45
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Thimme R. T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine. J Hepatol 2021; 74:220-229. [PMID: 33002569 DOI: 10.1016/j.jhep.2020.09.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.
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Affiliation(s)
- Robert Thimme
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Medical Center - University of Freiburg, Faculty of Medicine, Germany.
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Girardi DM, Pacífico JPM, Guedes de Amorim FPL, dos Santos Fernandes G, Teixeira MC, Pereira AAL. Immunotherapy and Targeted Therapy for Hepatocellular Carcinoma: A Literature Review and Treatment Perspectives. Pharmaceuticals (Basel) 2020; 14:28. [PMID: 33396181 PMCID: PMC7824026 DOI: 10.3390/ph14010028] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Advanced hepatocellular carcinoma is a prevalent and potentially aggressive disease. For more than a decade, treatment with sorafenib has been the only approved therapeutic approach. Moreover, no agent has been proven to prolong survival following the progression of disease after sorafenib treatment. However, in recent years, this scenario has changed substantially with several trials being conducted to examine the effects of immunotherapy and novel targeting agents. Several immune checkpoint inhibitors have shown promising results in early-stage clinical trials. Moreover, phase III trials with large cohorts have demonstrated remarkable improvement in survival with the use of new targeted therapies in second-line treatment. Treatment regimens involving the combination of two immune checkpoint inhibitors as well as immune checkpoint inhibitors and anti-angiogenic targeted therapies have shown potential to act synergistically in clinical trials. Recently, the combination of atezolizumab and bevacizumab evaluated in a phase III clinical trial has demonstrated survival superiority in the first-line treatment; it is the new considered standard of care. In this manuscript, we aimed to review the latest advances in the systemic treatment of advanced hepatocellular carcinoma focusing on immunotherapy and targeted therapies.
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Affiliation(s)
- Daniel M. Girardi
- Hospital Sírio-Libanes, SGAS 613/614 Conjunto E Lote 95-Asa Sul, Brasília 70200-730, Brazil; (G.d.S.F.); (A.A.L.P.)
- Hospital de Base do Distrito Federal, SMHS-Área Especial, Q. 101-Asa Sul, Brasília 70330-150, Brazil;
| | - Jana Priscila M. Pacífico
- Escola Superior de Ciências em Saúde, SMHN Conjunto A Bloco 01 Edifício Fepecs-Asa Norte, Brasília 70710-907, Brazil; (J.P.M.P.); (F.P.L.G.d.A.)
| | - Fernanda P. L. Guedes de Amorim
- Escola Superior de Ciências em Saúde, SMHN Conjunto A Bloco 01 Edifício Fepecs-Asa Norte, Brasília 70710-907, Brazil; (J.P.M.P.); (F.P.L.G.d.A.)
| | - Gustavo dos Santos Fernandes
- Hospital Sírio-Libanes, SGAS 613/614 Conjunto E Lote 95-Asa Sul, Brasília 70200-730, Brazil; (G.d.S.F.); (A.A.L.P.)
| | - Marcela C. Teixeira
- Hospital de Base do Distrito Federal, SMHS-Área Especial, Q. 101-Asa Sul, Brasília 70330-150, Brazil;
- Hospital DF Star, SGAS I SGAS 914-Asa Sul, Brasília 70390-140, Brazil
| | - Allan A. L. Pereira
- Hospital Sírio-Libanes, SGAS 613/614 Conjunto E Lote 95-Asa Sul, Brasília 70200-730, Brazil; (G.d.S.F.); (A.A.L.P.)
- Hospital de Base do Distrito Federal, SMHS-Área Especial, Q. 101-Asa Sul, Brasília 70330-150, Brazil;
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Perpiñán E, Pérez-Del-Pulgar S, Londoño MC, Mariño Z, Lens S, Leonel T, Bartres C, García-López M, Rodriguez-Tajes S, Forns X, Koutsoudakis G. Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus-specific CD8 + T cells after direct-acting antiviral therapies. J Viral Hepat 2020; 27:1408-1418. [PMID: 32812325 DOI: 10.1111/jvh.13370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/03/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C virus (HCV) infection impairs HCV CD8+ T-cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus-specific CD8+ T cells occurs after direct-acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow-up [FU] 12 and FU48) of virus-specific CD8+ T cells by multicolour flow cytometry in HCV-cirrhotic patients undergoing DAA therapy (n = 26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA-A*02. HCV noncirrhotic patients (n = 9) and healthy individuals (n = 10) served as controls. We found that the proliferative capacity of HCV-specific CD8+ T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down-regulation of inhibitory co-regulatory receptors in HCV-cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV-specific CD8+ T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the 'exhausted' phenotype in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients did not associate with their functions. Larger studier with longer follow-up may elucidate whether this complex interplay influences the outcome of cirrhotic patients.
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Affiliation(s)
- Elena Perpiñán
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sofía Pérez-Del-Pulgar
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - María-Carlota Londoño
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Thais Leonel
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Concepción Bartres
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Mireia García-López
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sergio Rodriguez-Tajes
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - George Koutsoudakis
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
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Okwor CIA, Oh JS, Crawley AM, Cooper CL, Lee SH. Expression of Inhibitory Receptors on T and NK Cells Defines Immunological Phenotypes of HCV Patients with Advanced Liver Fibrosis. iScience 2020; 23:101513. [PMID: 32920488 PMCID: PMC7492990 DOI: 10.1016/j.isci.2020.101513] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/23/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic HCV can result in advanced liver disease, including cirrhosis. Patients with advanced fibrosis experience poor clinical outcomes and increased risk for hepatocellular carcinoma (HCC). These outcomes are, in part, a consequence of immune dysfunction. Increased inhibitory receptor and Galectin-9 (GAL-9) expression is a possible mechanism promoting lymphocyte dysfunction. In this study, we measured the expression of inhibitory receptors and GAL-9 on T/NK cells of patients with chronic HCV with no to moderate fibrosis (F0-F2) and advanced fibrosis (F3-F4). To analyze their co-expression, we employed t-SNE analysis. Notably, we found that F3-F4 patients had higher frequencies of >3 inhibitory receptor co-expression on NK cells. Moreover, F3-F4 patients manifest a higher frequency of NK cells co-expressing TIGIT and TIM-3, and CD4/NK cells co-expressing LAG-3 and GAL-9. In conclusion, we identified phenotypes of immune dysregulation that could explain the increased susceptibility to infection and HCC in patients with chronic HCV with advanced fibrosis.
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Affiliation(s)
| | - Jun Seok Oh
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
| | - Angela Marie Crawley
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Department of Biology, Carleton University, Ottawa K1S 5B6, Canada
| | - Curtis Lindsey Cooper
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Department of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa K1G 5Z3, Canada
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
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Bukovsky A. Immunology of tissue homeostasis, ovarian cancer growth and regression, and long lasting cancer immune prophylaxis - review of literature. Histol Histopathol 2020; 36:31-46. [PMID: 32896865 DOI: 10.14670/hh-18-261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Data on the substantial physiological role of the immune system in the organism's ability to manage proper differentiation and function of normal tissues (tissue homeostasis), and detailed causes of the immune system's essential role for the in-vivo stimulation of cancer growth, are severely lacking. This results in a lack of effective cancer immunotherapy without adverse events, and in the lack of long-lasting cancer immune prophylaxes, particularly in ovarian cancers. Elimination of blood auto-antibodies blocking anti-cancer T cell effectors by intermittent moderate doses of cyclophosphamide, facilitation of the immune system reactivity against alloantigens of cancer cells by two subsequent blood transfusions, and augmentation of anticancer immunity by weekly intradermal injections of bacterial toxins, caused during the subsequent treatment-free period, lasting for two to four weeks, regression of inoperable epithelial ovarian cancers and regeneration of the tremendously metastatically altered abdominal tissues into normal healthy conditions without multivisceral cytoreductive surgery, which can result in life-threatening consequences. An otherwise untreated rectal cancer, progressing over 3 years, regressed after severe toxic dermatitis lasting over one week. This was caused by an accidental consumption of a large raw shiitake mushroom. Subsequent daily consumptions of 2 g Metformin ER and honeybee propolis ethanol extract, and weekly single larger raw shiitake mushroom, which all stimulate immune system reactivity against cancer stem cells, prevented malignant recurrence over the next 29 years without recurring dermatitis, and maintained healthy organism's conditions. These observations indicate that regression of advanced inoperable cancers and long-lasting cancer immune prophylaxis can be reached by simple approaches.
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Affiliation(s)
- Antonin Bukovsky
- Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, Vestec, Czech Republic.
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Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21176302. [PMID: 32878115 PMCID: PMC7504231 DOI: 10.3390/ijms21176302] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.
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