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Meyiah A, Al-Harrasi A, Ur Rehman N, Elkord E. Effect of boswellic acids on the expression of PD-1 and TIGIT immune checkpoints on activated human T cells. Fitoterapia 2025; 181:106401. [PMID: 39909360 DOI: 10.1016/j.fitote.2025.106401] [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: 10/08/2024] [Revised: 01/20/2025] [Accepted: 02/01/2025] [Indexed: 02/07/2025]
Abstract
Boswellic acids (BAs) have been documented as anti-inflammatory agents with the potential to regulate immune responses. However, their impacts on the expression level of immune checkpoint (IC) molecules in T cells have never been reported. By using flow cytometric assays, we investigated whether BAs extracted from Boswellia sacra (B. sacra) have any potential effects on the expression of PD-1 and TIGIT immune checkpoints (ICs) on activated T cells in vitro. Interestingly β-BA at a concentration of 50 μM significantly reduced the expression of PD-1 and TIGIT on both activated CD4+ and CD8+ T cells without any cytotoxicity. Additionally, β-KBA significantly reduced the percentages of CD4+PD-1+ and CD8+TIGIT+ T cells at 50 μM concentration. Furthermore, a significant reduction in CD4+PD-1+ T cells was observed following treatment with a lower concentration (25 μM) of β-AKBA. These findings show that BA compounds have the ability to reduce the expression of PD-1 and TIGIT in stimulated human T cells, which might play critical roles in reinvigorating exhausted T cells, indicating their potentials in immunosuppressed disease settings such as cancers and infections. This study is the first to investigate the effects of these compounds on the expression of immune checkpoints in human T cells. Clearly, further investigations are required to assess the mechanism of action of these compounds on ICs, and their efficacy as therapeutic agents in different diseases.
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Affiliation(s)
- Abdo Meyiah
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Oman
| | - Eyad Elkord
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China; College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates; Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, United Kingdom.
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King HAD, Lewin SR. Immune checkpoint inhibitors in infectious disease. Immunol Rev 2024; 328:350-371. [PMID: 39248154 PMCID: PMC11659942 DOI: 10.1111/imr.13388] [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] [Indexed: 09/10/2024]
Abstract
Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection. We highlight several key studies and future directions of research in relation to anti-PD-1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV-specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti-PD-1 and anti-CTLA-4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti-PD-1 in vivo in people with HIV on ART without cancer and potential combinations of anti-PD-1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers.
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Affiliation(s)
- Hannah A. D. King
- Department of Infectious DiseasesThe University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
| | - Sharon R. Lewin
- Department of Infectious DiseasesThe University of Melbourne at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
- Victorian Infectious Diseases ServiceRoyal Melbourne Hospital at The Peter Doherty Institute for Infection and ImmunityMelbourneVictoriaAustralia
- Department of Infectious DiseasesAlfred Hospital and Monash UniversityMelbourneVictoriaAustralia
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BATOROV EGORV, INESHINA ALISAD, ARISTOVA TATIANAA, DENISOVA VERAV, SIZIKOVA SVETLANAA, BATOROVA DARIAS, USHAKOVA GALINAY, SHEVELA EKATERINAY, CHERNYKH ELENAR. PD-1 + and TIM-3 + T cells widely express common γ-chain cytokine receptors in multiple myeloma patients, and IL-2, IL-7, IL-15 stimulation up-regulates PD-1 and TIM-3 on T cells. Oncol Res 2024; 32:1575-1587. [PMID: 39308517 PMCID: PMC11413821 DOI: 10.32604/or.2024.047893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/09/2024] [Indexed: 09/25/2024] Open
Abstract
Background Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma (MM) progression. Simultaneously, previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with common γ-chain family cytokines in vitro and during homeostatic proliferation. The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets up-regulating PD-1 and TIM-3 checkpoint molecules. Methods The expression of CD25, CD122, CD127 common γ-chain cytokine receptors, phosphorylated signal transducer and activator of transcription-5 (pSTAT5) and eomesodermin (EOMES) was comparatively assessed with flow cytometry in PD-1- and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients. Results Substantial proportions of PD-1- and TIM-3-positive T lymphocytes expressed common γ-chain cytokine receptors and pSTAT5. Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+ T cells compared to PD-1+TIM-3- subsets. Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+ T cells express EOMES, while only moderate frequencies of CD4+ PD-1+/TIM-3+ T cells up-regulate this transcription factor. Besides, the surface presence of CD25 and intranuclear expression of EOMES in CD4+ T cells were mutually exclusive regardless of PD-1 and TIM-3 expression. The stimulation with common γ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+ and TIM-3+ T cell subsets in vitro. Conclusions Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation. Differences in common γ-chain cytokine receptor expression between PD-1+ and TIM-3+ T cells may reflect functional dissimilarity of these cell subsets. Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+ T cells but may raise the possibility of immune-mediated adverse events.
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Affiliation(s)
- EGOR V. BATOROV
- Laboratory of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
- V. Zelman Institute of Medicine and Psychology, Novosibirsk National Research State University, Novosibirsk, 630090, Russia
| | - ALISA D. INESHINA
- V. Zelman Institute of Medicine and Psychology, Novosibirsk National Research State University, Novosibirsk, 630090, Russia
| | - TATIANA A. ARISTOVA
- Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - VERA V. DENISOVA
- Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - SVETLANA A. SIZIKOVA
- Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - DARIA S. BATOROVA
- Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - GALINA Y. USHAKOVA
- Department of Hematology and Bone Marrow Transplantation, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - EKATERINA Y. SHEVELA
- Laboratory of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
| | - ELENA R. CHERNYKH
- Laboratory of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, 630099, Russia
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Narmada BC, Khakpoor A, Shirgaonkar N, Narayanan S, Aw PPK, Singh M, Ong KH, Owino CO, Ng JWT, Yew HC, Binte Mohamed Nasir NS, Au VB, Sng R, Kaliaperumal N, Khine HHTW, di Tocco FC, Masayuki O, Naikar S, Ng HX, Chia SL, Seah CXY, Alnawaz MH, Wai CLY, Tay AYL, Mangat KS, Chew V, Yu W, Connolly JE, Periyasamy G, Plissonnier ML, Levrero M, Lim SG, DasGupta R. Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity. J Hepatol 2024; 81:42-61. [PMID: 38423478 DOI: 10.1016/j.jhep.2024.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/05/2024] [Accepted: 02/15/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND & AIMS Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC. METHODS We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC. RESULTS We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC. CONCLUSIONS Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis. IMPACT AND IMPLICATIONS This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B.
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Affiliation(s)
- Balakrishnan Chakrapani Narmada
- Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672; Experimental Drug Development Centre, A∗STAR, 10 Biopolis Way, Chromos, Singapore 138670, Singapore
| | - Atefeh Khakpoor
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Niranjan Shirgaonkar
- Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672
| | - Sriram Narayanan
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Pauline Poh Kim Aw
- Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672
| | - Malay Singh
- Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore
| | - Kok Haur Ong
- Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore
| | - Collins Oduor Owino
- Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jane Wei Ting Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hui Chuing Yew
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Veonice Bijin Au
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Reina Sng
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Nivashini Kaliaperumal
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Htet Htet Toe Wai Khine
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Otsuka Masayuki
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore
| | - Shamita Naikar
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore
| | - Hui Xin Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Su Li Chia
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Myra Hj Alnawaz
- Department of Medicine, National University Hospital, Singapore
| | - Chris Lee Yoon Wai
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Amy Yuh Ling Tay
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kamarjit Singh Mangat
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore
| | - Weimiao Yu
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Bioinformatics Institute, A∗STAR, 30 Biopolis Street, Matrix, Singapore 138671, Singapore
| | - John Edward Connolly
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Biomedical Studies, Baylor University, Waco, TX, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Giridharan Periyasamy
- Experimental Drug Development Centre, A∗STAR, 10 Biopolis Way, Chromos, Singapore 138670, Singapore
| | | | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France; Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France; University of Lyon Claude Bernard 1 (UCLB1), Lyon, France; Department of Medicine SCIAC and the Italian Institute of Technology (IIT) Center for Life Nanosciences (CLNS), University of Rome La Sapienza, Rome, Italy
| | - Seng Gee Lim
- Institute of Molecular and Cell Biology, A∗STAR, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore; Department of Medicine, National University Hospital, Singapore; Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore.
| | - Ramanuj DasGupta
- Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology and Research (A∗STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672.
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Martín-Martín C, del Riego ES, Castiñeira JRV, Zapico-Gonzalez MS, Rodríguez-Pérez M, Corte-Iglesias V, Saiz ML, Diaz-Bulnes P, Escudero D, Suárez-Alvarez B, López-Larrea C. Assessing Predictive Value of SARS-CoV-2 Epitope-Specific CD8 + T-Cell Response in Patients with Severe Symptoms. Vaccines (Basel) 2024; 12:679. [PMID: 38932408 PMCID: PMC11209605 DOI: 10.3390/vaccines12060679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/10/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Specific T cell responses against SARS-CoV-2 provided an overview of acquired immunity during the pandemic. Anti-SARS-CoV-2 immunity determines the severity of acute illness, but also might be related to the possible persistence of symptoms (long COVID). We retrospectively analyzed ex vivo longitudinal CD8+ T cell responses in 26 COVID-19 patients diagnosed with severe disease, initially (1 month) and long-term (10 months), and in a cohort of 32 vaccinated healthcare workers without previous SARS-CoV-2 infection. We used peptide-human leukocyte antigen (pHLA) dextramers recognizing 26 SARS-CoV-2-derived epitopes of viral and other non-structural proteins. Most patients responded to at least one of the peptides studied, mainly derived from non-structural ORF1ab proteins. After 10 months follow-up, CD8+ T cell responses were maintained at long term and reaction against certain epitopes (A*01:01-ORF1ab1637) was still detected and functional, showing a memory-like phenotype (CD127+ PD-1+). The total number of SARS-CoV-2-specific CD8+ T cells was significantly associated with protection against long COVID in these patients. Compared with vaccination, infected patients showed a less effective immune response to spike protein-derived peptides restricted by HLA. So, the A*01:01-S865 and A*24:02-S1208 dextramers were only recognized in vaccinated individuals. We conclude that initial SARS-CoV-2-specific CD8+ T cell response could be used as a marker to understand the evolution of severe disease and post-acute sequelae after SARS-CoV-2 infection.
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Affiliation(s)
- Cristina Martín-Martín
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
| | - Estefanía Salgado del Riego
- Service of Intensive Medicine, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (E.S.d.R.); (D.E.)
- Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain
| | - Jose R. Vidal Castiñeira
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
- Immunology Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | | | - Mercedes Rodríguez-Pérez
- Microbiology Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (M.S.Z.-G.); (M.R.-P.)
- Translational Microbiology, Health Research Institute of Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Viviana Corte-Iglesias
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
- Immunology Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Maria Laura Saiz
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
| | - Paula Diaz-Bulnes
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
| | - Dolores Escudero
- Service of Intensive Medicine, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (E.S.d.R.); (D.E.)
- Translational Microbiology, Health Research Institute of Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Beatriz Suárez-Alvarez
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
| | - Carlos López-Larrea
- Translational Immunology, Health Research Institute of the Principality of Asturias (ISPA), Avenida de Roma S/N, 33011 Oviedo, Spain; (C.M.-M.); (J.R.V.C.); (V.C.-I.); (M.L.S.); (P.D.-B.)
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Li J, Vranjkovic A, Read D, Delaney SP, Stanford WL, Cooper CL, Crawley AM. Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction. Front Immunol 2024; 15:1375485. [PMID: 38887299 PMCID: PMC11180750 DOI: 10.3389/fimmu.2024.1375485] [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: 01/23/2024] [Accepted: 04/19/2024] [Indexed: 06/20/2024] Open
Abstract
Background The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
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Affiliation(s)
- Jiafeng Li
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
| | - Agatha Vranjkovic
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Daniel Read
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Sean P. Delaney
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - William L. Stanford
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Curtis L. Cooper
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Angela M. Crawley
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada
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Borhani K, Bamdad T, Hashempour A, Salek Farrokhi A, Moayedi J. Comparison of the inhibitory and stimulatory effects of Core and NS3 candidate HCV vaccines on the cellular immune response. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2023; 12:153-163. [PMID: 38187363 PMCID: PMC10767197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/16/2023] [Indexed: 01/09/2024]
Abstract
Currently, hepatitis C virus (HCV) infects nearly 3% of the global population, the majority of whom are chronically infected; however, hepatitis C vaccines are still in the developmental stage. Numerous studies suggest that the spontaneous resolution of HCV infection and the design of its vaccine are reliant on vital contributions from CTL cell responses and T regulatory cells. Multiple researchers have identified both Core and nonstructural protein 3 (NS3) proteins as crucial immune genes and potential candidates for HCV DNA vaccine design. In this study, Core and NS3 were subcloned and inserted into pcDNA3.1 to construct HCV DNA vaccines administered in mouse models. Furthermore, the effects of Core and NS3 on the induction of CTL and NK were compared in spleen mouse models using the LDH method. Additionally, flow cytometry was employed to investigate the percentage of T regulatory cells (Treg cells) and cells expressing PD-1 in the spleens of the mouse models. Our data indicated that pcDNA3.1+NS3 and pcDNA3.1+Core could enhance CTL and NK activity in mouse models. Importantly, the Treg and PD-1 analysis in mouse models revealed a substantial reduction in the proportions of CD4+/CD25+/Foxp3+ T cells and PD-1+ cells in experimental subjects treated with HCV NS3 along with 5 mg/kg of lenalidomide, utilized as a novel adjuvant, compared to those administered an equivalent dosage of lenalidomide in conjunction with HCV Core. In conclusion, our observations indicated that the NS3-HCV gene had a limited impact on the activation of inhibitory factors. Therefore, NS3 is considered a more suitable candidate for DNA vaccine design compared to Core HCV.
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Affiliation(s)
- Kiandokht Borhani
- Department of Virology, School of Medical Sciences, Tarbiat Modares UniversityTehran, Iran
| | - Taravat Bamdad
- Department of Virology, School of Medical Sciences, Tarbiat Modares UniversityTehran, Iran
| | - Ava Hashempour
- Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical SciencesShiraz, Iran
| | - Amir Salek Farrokhi
- Department of Immunology, School of Medical Sciences, Tarbiat Modares UniversityTehran, Iran
| | - Javad Moayedi
- Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical SciencesShiraz, Iran
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8
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Chen Y, Xu Z, Sun H, Ouyang X, Han Y, Yu H, Wu N, Xie Y, Su B. Regulation of CD8 + T memory and exhaustion by the mTOR signals. Cell Mol Immunol 2023; 20:1023-1039. [PMID: 37582972 PMCID: PMC10468538 DOI: 10.1038/s41423-023-01064-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 07/02/2023] [Indexed: 08/17/2023] Open
Abstract
CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.
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Affiliation(s)
- Yao Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ziyang Xu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hongxiang Sun
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xinxing Ouyang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Tumor Biology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuheng Han
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Haihui Yu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ningbo Wu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yiting Xie
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Bing Su
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and The Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Tumor Biology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Key Laboratory of Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China.
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9
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Mulik S, Berber E, Sehrawat S, Rouse BT. Controlling viral inflammatory lesions by rebalancing immune response patterns. Front Immunol 2023; 14:1257192. [PMID: 37671156 PMCID: PMC10475736 DOI: 10.3389/fimmu.2023.1257192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/07/2023] [Indexed: 09/07/2023] Open
Abstract
In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many chronic viral infections. We make the point that in several viral infections the lesions can be largely the result of one or more aspects of the host response mediating the cell and tissue damage rather than the virus itself being directly responsible. However, within the reactive inflammatory lesions along with the pro-inflammatory participants there are also other aspects of the host response that may be acting to constrain the activity of the damaging components and are contributing to resolution. This scenario should provide the prospect of rebalancing the contributions of different host responses and hence diminish or even fully control the virus-induced lesions. We identify several aspects of the host reactions that influence the pattern of immune responsiveness and describe approaches that have been used successfully, mainly in model systems, to modulate the activity of damaging participants and which has led to lesion control. We emphasize examples where such therapies are, or could be, translated for practical use in the clinic to control inflammatory lesions caused by viral infections.
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Affiliation(s)
- Sachin Mulik
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX, United States
| | - Engin Berber
- Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Sharvan Sehrawat
- Indian Institute of Science Education and Research, Department of Biological Sciences, Mohali, Punjab, India
| | - Barry Tyrrell Rouse
- College of Veterinary Medicine, University of Tennessee, Knoxville, TN, United States
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10
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Shoukry NH, Cox AL, Walker CM. Immunological Monitoring in Hepatitis C Virus Controlled Human Infection Model. Clin Infect Dis 2023; 77:S270-S275. [PMID: 37579206 PMCID: PMC10425133 DOI: 10.1093/cid/ciad359] [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] [Indexed: 08/16/2023] Open
Abstract
Controlled human infection model trials for hepatitis C virus represent an important opportunity to identify correlates of protective immunity against a well-characterized inoculum of hepatitis C virus and how such responses are modified by vaccination. In this article, we discuss the approach to immunological monitoring during such trials, including a set of recommendations for optimal sampling schedule and preferred immunological assays to examine the different arms of the immune response. We recommend that this approach be adapted to different trial designs. Finally, we discuss how these studies can provide surrogate predictors of the success of candidate vaccines.
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Affiliation(s)
- Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Département de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher M Walker
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
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11
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Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther 2023; 8:235. [PMID: 37332039 PMCID: PMC10277291 DOI: 10.1038/s41392-023-01471-y] [Citation(s) in RCA: 266] [Impact Index Per Article: 133.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 06/20/2023] Open
Abstract
T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.
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Affiliation(s)
- Lina Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Xin Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China.
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China.
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12
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Dulal D, Boring A, Terrero D, Johnson T, Tiwari AK, Raman D. Tackling of Immunorefractory Tumors by Targeting Alternative Immune Checkpoints. Cancers (Basel) 2023; 15:2774. [PMID: 37345111 PMCID: PMC10216651 DOI: 10.3390/cancers15102774] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/09/2023] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
Physiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor microenvironment through expression of cognate ligands for the ICs present on the cell surface of CD8+ T lymphocytes. The ligation of ICs on CD8+ T lymphocytes triggers inhibitory signaling pathways, leading to quiescence or an exhaustion of CD8+ T lymphocytes. This results in failure of immunotherapy. To overcome this, several FDA-approved therapeutic antibodies are available, but the clinical outcome is quite variable due to the resistance encountered through upregulated expression of alternate ICs such as VISTA, LAG-3, TIGIT and TIM-3. This review focuses on the roles played by the traditional as well as alternate ICs and the contribution of associated signaling pathways in generating such resistance to immunotherapy. Combinatorial targeting of traditional and alternate ICs might be beneficial for immune-refractory tumors.
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Affiliation(s)
- Dharmindra Dulal
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA; (D.D.); (A.B.); (A.K.T.)
| | - Andrew Boring
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA; (D.D.); (A.B.); (A.K.T.)
| | - David Terrero
- Department of Pharmacology & Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo Main Campus, Toledo, OH 43614, USA
| | - Tiffany Johnson
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA; (D.D.); (A.B.); (A.K.T.)
| | - Amit K. Tiwari
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA; (D.D.); (A.B.); (A.K.T.)
- Department of Pharmacology & Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo Main Campus, Toledo, OH 43614, USA
| | - Dayanidhi Raman
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614, USA; (D.D.); (A.B.); (A.K.T.)
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13
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Kasmani MY, Zander R, Chung HK, Chen Y, Khatun A, Damo M, Topchyan P, Johnson KE, Levashova D, Burns R, Lorenz UM, Tarakanova VL, Joshi NS, Kaech SM, Cui W. Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection. J Exp Med 2023; 220:e20220679. [PMID: 36315049 PMCID: PMC9623343 DOI: 10.1084/jem.20220679] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/17/2022] [Accepted: 08/08/2022] [Indexed: 11/05/2022] Open
Abstract
Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion.
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Affiliation(s)
- Moujtaba Y. Kasmani
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Ryan Zander
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - H. Kay Chung
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
| | - Yao Chen
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Achia Khatun
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Martina Damo
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT
| | - Paytsar Topchyan
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Kaitlin E. Johnson
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Darya Levashova
- Department of Microbiology, Immunology, and Cancer Biology, and Carter Immunology Center, University of Virginia, Charlottesville, VA
| | - Robert Burns
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
| | - Ulrike M. Lorenz
- Department of Microbiology, Immunology, and Cancer Biology, and Carter Immunology Center, University of Virginia, Charlottesville, VA
| | - Vera L. Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Nikhil S. Joshi
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT
| | - Susan M. Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA
| | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI
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14
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Najafi S, Majidpoor J, Mortezaee K. The impact of microbiota on PD-1/PD-L1 inhibitor therapy outcomes: A focus on solid tumors. Life Sci 2022; 310:121138. [DOI: 10.1016/j.lfs.2022.121138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/02/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
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15
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Ando S, Araki K. CD8 T cell heterogeneity during T cell exhaustion and PD-1-targeted immunotherapy. Int Immunol 2022; 34:571-577. [PMID: 35901837 PMCID: PMC9533227 DOI: 10.1093/intimm/dxac038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/25/2022] [Indexed: 11/12/2022] Open
Abstract
Persistent antigenic stimulation results in loss of effector function or physical deletion of antigen-specific CD8 T cells. This T cell state is called T cell exhaustion and occurs during chronic infection and cancer. Antigen-specific CD8 T cells during T cell exhaustion express the inhibitory receptor PD-1, the expression of which plays a major role in T cell dysfunction. PD-1 blockade re-invigorates CD8 T cell immunity and has been proven effective against many different types of human cancer. To further improve the efficacy of PD-1-targeted immunotherapy in cancer patients, a better understanding of T cell exhaustion is required. Recent studies have revealed that antigen-specific CD8 T cells during T cell exhaustion are heterogeneous and have also uncovered the detailed mechanisms for PD-1-targeted immunotherapy. Here, we review the CD8 T cell subsets that arise during T cell exhaustion, the lineage relationship among these individual subsets and the role of each subset in PD-1 blockade. Also, we discuss potential strategies to enhance the efficacy of PD-1-targeted immunotherapy.
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Affiliation(s)
- Satomi Ando
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, 45229 OH, USA
| | - Koichi Araki
- Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, 45229 OH, USA
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16
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Hepatitis B virus reactivation in patients undergoing immune checkpoint inhibition: systematic review with meta-analysis. J Cancer Res Clin Oncol 2022; 149:1993-2008. [PMID: 35767193 DOI: 10.1007/s00432-022-04133-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/10/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy. METHODS A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection. CONCLUSIONS Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.
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17
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Chaudhary O, Trotta D, Wang K, Wang X, Chu X, Bradley C, Okulicz J, Maves RC, Kronmann K, Schofield CM, Blaylock JM, Deng Y, Schalper KA, Kaech SM, Agan B, Ganesan A, Emu B. Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis. J Immunother Cancer 2022; 10:jitc-2022-004564. [PMID: 35470232 PMCID: PMC9039380 DOI: 10.1136/jitc-2022-004564] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND People living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a marker of risk for cancer among HIV-infected virally suppressed patients. METHODS A nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point. RESULTS We found that cases have increased expression of PD-1 +CD160+CD244+ ('triple positive') on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-betdimEomeshi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion. CONCLUSION In conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-betdimEomeshi, that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH.
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Affiliation(s)
- Omkar Chaudhary
- Internal Medicine; Infectious Disease, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Diane Trotta
- Flow Cytometry Facility, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kaicheng Wang
- School of Public Health, Yale University, New Haven, Connecticut, USA
| | - Xun Wang
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Internal Medicine; Infectious Diseases and Critical Care, Naval Medical Center San Diego, San Diego, California, USA
| | - Xiuping Chu
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Internal Medicine; Infectious Diseases and Critical Care, Naval Medical Center San Diego, San Diego, California, USA
| | - Chip Bradley
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Internal Medicine; Infectious Diseases and Critical Care, Naval Medical Center San Diego, San Diego, California, USA
| | - Jason Okulicz
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas, USA
| | - Ryan C Maves
- Internal Medicine; Infectious Diseases and Critical Care, Naval Medical Center San Diego, San Diego, California, USA
| | - Karl Kronmann
- Internal Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
| | - Christina M Schofield
- Internal Medicine; Infectious Diseases, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Jason M Blaylock
- Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Yanhong Deng
- School of Public Health, Yale University, New Haven, Connecticut, USA
| | - Kurt A Schalper
- Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Susan M Kaech
- Departments of Immunobiology, Salk Institute, La Jolla, California, USA
| | - Brian Agan
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Internal Medicine; Infectious Diseases and Critical Care, Naval Medical Center San Diego, San Diego, California, USA
| | - Anuradha Ganesan
- Infectious Disease Clinical Research Program, Bethesda, Maryland, USA,Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Brinda Emu
- Internal Medicine; Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, USA,Internal Medicine; Infectious Diseases, VA Connecticut Healthcare System - West Haven Campus, West Haven, Connecticut, USA
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18
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Timofeeva A, Sedykh S, Nevinsky G. Post-Immune Antibodies in HIV-1 Infection in the Context of Vaccine Development: A Variety of Biological Functions and Catalytic Activities. Vaccines (Basel) 2022; 10:384. [PMID: 35335016 PMCID: PMC8955465 DOI: 10.3390/vaccines10030384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
Unlike many other viruses, HIV-1 is highly variable. The structure of the viral envelope changes as the infection progresses and is one of the biggest obstacles in developing an HIV-1 vaccine. HIV-1 infection can cause the production of various natural autoantibodies, including catalytic antibodies hydrolyzing DNA, myelin basic protein, histones, HIV-integrase, HIV-reverse transcriptase, β-casein, serum albumin, and some other natural substrates. Currently, there are various directions for the development of HIV-1 vaccines: stimulation of the immune response on the mucous membranes; induction of cytotoxic T cells, which lyse infected cells and hold back HIV-infection; immunization with recombinant Env proteins or vectors encoding Env; mRNA-based vaccines and some others. However, despite many attempts to develop an HIV-1 vaccine, none have been successful. Here we review the entire spectrum of antibodies found in HIV-infected patients, including neutralizing antibodies specific to various viral epitopes, as well as antibodies formed against various autoantigens, catalytic antibodies against autoantigens, and some viral proteins. We consider various promising targets for developing a vaccine that will not produce unwanted antibodies in vaccinated patients. In addition, we review common problems in the development of a vaccine against HIV-1.
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Affiliation(s)
- Anna Timofeeva
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (S.S.); (G.N.)
| | - Sergey Sedykh
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (S.S.); (G.N.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Georgy Nevinsky
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; (S.S.); (G.N.)
- Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
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19
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Abstract
Exhaustion of T cells occurs in response to long-term exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T-cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers' expression. Recent studies have begun to elucidate the role of T-cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T-cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Among the drugs that are widely used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance.
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20
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Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
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Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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21
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Halma J, Pierce S, McLennan R, Bradley T, Fischer R. Natural killer cells in liver transplantation: Can we harness the power of the immune checkpoint to promote tolerance? Clin Transl Sci 2021; 15:1091-1103. [PMID: 34866338 PMCID: PMC9099129 DOI: 10.1111/cts.13208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 08/30/2021] [Accepted: 11/14/2021] [Indexed: 11/29/2022] Open
Abstract
The roles that natural killer (NK) cells play in liver disease and transplantation remain ill‐defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK‐mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro‐environment. In this review, we summarize NK cell populations in the peripheral blood and liver, and we explore the data regarding the expression and function of immune checkpoint molecules on NK cells. We also hypothesize about the roles they could play in liver transplantation and discuss how they might be harnessed therapeutically in transplant sciences.
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Affiliation(s)
- Jennifer Halma
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Stephen Pierce
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Rebecca McLennan
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Todd Bradley
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Ryan Fischer
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
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22
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Kefalakes H, Horgan XJ, Jung MK, Amanakis G, Kapuria D, Bolte FJ, Kleiner DE, Koh C, Heller T, Rehermann B. Liver-Resident Bystander CD8 + T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection. Gastroenterology 2021; 161:1567-1583.e9. [PMID: 34302839 DOI: 10.1053/j.gastro.2021.07.027] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 06/29/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The hepatitis D virus (HDV) causes the most severe form of chronic hepatitis, often progressing to cirrhosis within 5 to 10 years. There is no curative treatment, and the mechanisms underlying the accelerated liver disease progression are unknown. METHODS Innate and adaptive immune responses were studied in blood and liver of 24 patients infected with HDV and 30 uninfected controls by multiparameter flow cytometry in correlation with disease severity and stage. RESULTS The 2 main intrahepatic innate immune-cell populations, mucosal-associated invariant T cells and natural killer (NK) cells, were reduced in the livers of patients infected with HDV compared with those of uninfected controls but were more frequently activated in the liver compared with the blood. Most intrahepatic cluster of differentiation (CD) 8-positive (CD8+) T cells were memory cells or terminal effector memory cells, and most of the activated and degranulating (CD107a+) HDV-specific and total CD8+ T cells were liver-resident (CD69+C-X-C motif chemokine receptor 6+). Unsupervised analysis of flow cytometry data identified an activated, memory-like, tissue-resident HDV-specific CD8+ T-cell cluster with expression of innate-like NK protein 30 (NKp30) and NK group 2D (NKG2D) receptors. The size of this population correlated with liver enzyme activity (r = 1.0). NKp30 and NKG2D expression extended beyond the HDV-specific to the total intrahepatic CD8+ T-cell population, suggesting global bystander activation. This was supported by the correlations between (i) NKG2D expression with degranulation of intrahepatic CD8+ T cells, (ii) frequency of degranulating CD8+ T cells with liver enzyme activity and the aspartate aminotransferase-to-platelet ratio index score, and by the in vitro demonstration of cytokine-induced NKG2D-dependent cytotoxicity. CONCLUSION Antigen-nonspecific activation of liver-resident CD8+ T cells may contribute to inflammation and disease stage in HDV infection.
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Affiliation(s)
- Helenie Kefalakes
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Xylia J Horgan
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Min Kyung Jung
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Georgios Amanakis
- Laboratory of Cardiac Physiology, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Devika Kapuria
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Fabian J Bolte
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Christopher Koh
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
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23
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Jimbu L, Mesaros O, Neaga A, Nanut AM, Tomuleasa C, Dima D, Bocsan C, Zdrenghea M. The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10-IL-10R Pathways in Acute Myeloid Leukemia. Pharmaceuticals (Basel) 2021; 14:1105. [PMID: 34832887 PMCID: PMC8620891 DOI: 10.3390/ph14111105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/17/2021] [Accepted: 10/25/2021] [Indexed: 12/30/2022] Open
Abstract
Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.
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Affiliation(s)
- Laura Jimbu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Oana Mesaros
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- “Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, 19-21 Croitorilor Str., 400162 Cluj-Napoca, Romania
| | - Alexandra Neaga
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
| | - Ana Maria Nanut
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
| | - Ciprian Tomuleasa
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Corina Bocsan
- Department of Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania;
| | - Mihnea Zdrenghea
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
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24
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Shoukry NH. Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV. Viruses 2021; 13:1871. [PMID: 34578451 PMCID: PMC8473057 DOI: 10.3390/v13091871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 12/23/2022] Open
Abstract
Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied to understand correlates of protective immunity against hepatitis C virus (HCV) infection and to inform vaccine development. This review focuses on recent progress in understanding immunity to HCV using systems biology, specifically transcriptomic and epigenetic studies. It also examines proposed strategies moving forward towards an integrated systems immunology approach for predicting and evaluating the efficacy of the next generation of HCV vaccines.
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Affiliation(s)
- Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Tour Viger, Local R09.414, 900 Rue St-Denis, Montréal, QC H2X 0A9, Canada;
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada
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25
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Brochado-Kith Ó, Martínez I, Berenguer J, González-García J, Salgüero S, Sepúlveda-Crespo D, Díez C, Hontañón V, Ibañez-Samaniego L, Pérez-Latorre L, Fernández-Rodríguez A, Ángeles Jiménez-Sousa M, Resino S. HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients. Front Immunol 2021; 12:723196. [PMID: 34497613 PMCID: PMC8419228 DOI: 10.3389/fimmu.2021.723196] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/06/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways (“cytokine-cytokine receptor interaction”, “viral protein interaction with cytokine and cytokine receptor”, “chemokine signaling pathway”, and “hepatitis C”). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.
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Affiliation(s)
- Óscar Brochado-Kith
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Juan Berenguer
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - Juan González-García
- Unidad de VIH, Servicio de Medicina Interna, Hospital Universitario "La Paz", Madrid, Spain.,Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Sergio Salgüero
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.,Unidad de Análisis Clínicos, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain
| | - Daniel Sepúlveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Cristina Díez
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - Víctor Hontañón
- Unidad de VIH, Servicio de Medicina Interna, Hospital Universitario "La Paz", Madrid, Spain.,Instituto de Investigación Sanitaria La Paz (IdiPAZ), Madrid, Spain
| | - Luis Ibañez-Samaniego
- Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain.,Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Leire Pérez-Latorre
- Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - María Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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26
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Jacob RA, Edgar CR, Prévost J, Trothen SM, Lurie A, Mumby MJ, Galbraith A, Kirchhoff F, Haeryfar SMM, Finzi A, Dikeakos JD. The HIV-1 accessory protein Nef increases surface expression of the checkpoint receptor Tim-3 in infected CD4 + T cells. J Biol Chem 2021; 297:101042. [PMID: 34358561 PMCID: PMC8390549 DOI: 10.1016/j.jbc.2021.101042] [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: 04/07/2021] [Revised: 07/28/2021] [Accepted: 08/02/2021] [Indexed: 12/17/2022] Open
Abstract
Prolonged immune activation drives the upregulation of multiple checkpoint receptors on the surface of virus-specific T cells, inducing their exhaustion. Reversing HIV-1-induced T cell exhaustion is imperative for efficient virus clearance; however, viral mediators of checkpoint receptor upregulation remain largely unknown. The enrichment of checkpoint receptors on T cells upon HIV-1 infection severely constrains the generation of an efficient immune response. Herein, we examined the role of HIV-1 Nef in mediating the upregulation of checkpoint receptors on peripheral blood mononuclear cells. We demonstrate that the HIV-1 accessory protein Nef upregulates cell surface levels of the checkpoint receptor T-cell immunoglobulin mucin domain-3 (Tim-3) and that this is dependent on Nef's dileucine motif LL164/165. Furthermore, we used a bimolecular fluorescence complementation assay to demonstrate that Nef and Tim-3 form a complex within cells that is abrogated upon mutation of the Nef dileucine motif. We also provide evidence that Nef moderately promotes Tim-3 shedding from the cell surface in a dileucine motif–dependent manner. Treating HIV-1-infected CD4+ T cells with a matrix metalloprotease inhibitor enhanced cell surface Tim-3 levels and reduced Tim-3 shedding. Finally, Tim-3-expressing CD4+ T cells displayed a higher propensity to release the proinflammatory cytokine interferon-gamma. Collectively, our findings uncover a novel mechanism by which HIV-1 directly increases the levels of a checkpoint receptor on the surface of infected CD4+ T cells.
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Affiliation(s)
- Rajesh Abraham Jacob
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Cassandra R Edgar
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Jérémie Prévost
- Centre de Recherche du CHUM, Montreal, Quebec, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada
| | - Steven M Trothen
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Antony Lurie
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Mitchell J Mumby
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Alexa Galbraith
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Frank Kirchhoff
- Institute of Molecular Virology, Ulm University Medical Center, UIm, Germany
| | - S M Mansour Haeryfar
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Andrés Finzi
- Centre de Recherche du CHUM, Montreal, Quebec, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
| | - Jimmy D Dikeakos
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
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27
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Fan L, Lei H, Lin Y, Zhou Z, Shu G, Yan Z, Chen H, Zhang T, Yin G. Identification of a Gene Set Correlated With Immune Status in Ovarian Cancer by Transcriptome-Wide Data Mining. Front Mol Biosci 2021; 8:670666. [PMID: 34395521 PMCID: PMC8363306 DOI: 10.3389/fmolb.2021.670666] [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] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 07/16/2021] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoint blocking (ICB) immunotherapy has achieved great success in the treatment of various malignancies. Although not have been approved for the treatment of ovarian cancer (OC), it has been actively tested for the treatment of OC. However, biomarkers that could indicate the immune status of OC and predict the response to ICB are rare. We downloaded RNAseq and clinical data of OC from The Cancer Genome Atlas (TCGA). Data analysis revealed both TMBhigh and immunityhigh were significantly related to better survival of OC. Up-regulated differentially expressed genes (Up-DEGs) were identified by analyzing the gene expression levels. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the "GSVA" and "limma" package in R software. The correlation of genes with overall survival was also analyzed by conducted Kaplan-Meier survival analysis. Four genes, CXCL13, FCRLA, MS4A1, and PLA2G2D were found positively correlated with better prognosis of OC and mainly involved in immune response-related pathways. Finally, TIMER and TIDE were used to predict gene immune function and its association with immunotherapy. We found that these four genes were positively correlated with better response to immune checkpoint blockade-based immunotherapy. Altogether, CXCL13, FCRLA, MS4A1, and PLA2G2D may be used as potential therapeutic genes for reflecting OC immune status and predicting response to immunotherapy.
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Affiliation(s)
- Lili Fan
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China.,School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Han Lei
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Ying Lin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Zhengwei Zhou
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Guang Shu
- School of Basic Medical Sciences, Central South University, Changsha, China
| | - Zhipeng Yan
- Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Haotian Chen
- School of Basic Medical Sciences, Central South University, Changsha, China
| | - Tianxiang Zhang
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China
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28
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Yates KB, Tonnerre P, Martin GE, Gerdemann U, Al Abosy R, Comstock DE, Weiss SA, Wolski D, Tully DC, Chung RT, Allen TM, Kim AY, Fidler S, Fox J, Frater J, Lauer GM, Haining WN, Sen DR. Epigenetic scars of CD8 + T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol 2021; 22:1020-1029. [PMID: 34312547 DOI: 10.1038/s41590-021-00979-1] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/17/2021] [Indexed: 12/12/2022]
Abstract
T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.
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Affiliation(s)
- Kathleen B Yates
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Pierre Tonnerre
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA.,Inserm U976, Institut de Recherche Saint-Louis, Paris, France
| | - Genevieve E Martin
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia
| | - Ulrike Gerdemann
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rose Al Abosy
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Dawn E Comstock
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
| | - Sarah A Weiss
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
| | - David Wolski
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - Damien C Tully
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.,Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Raymond T Chung
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - Todd M Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
| | - Sarah Fidler
- Division of Medicine, Wright Fleming Institute, Imperial College, London, UK.,Imperial College National Institute for Health Research Biomedical Research Centre, London, UK
| | - Julie Fox
- Department of Genitourinary Medicine and Infectious Disease, Guy's and St Thomas' NHS Foundation Trust, London, UK.,King's College National Institute for Health Research Biomedical Research Centre, London, UK
| | - John Frater
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
| | - Georg M Lauer
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - W Nicholas Haining
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .,Merck Research Laboratories, Boston, MA, USA.
| | - Debattama R Sen
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .,Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
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29
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Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial. Viruses 2021; 13:v13071351. [PMID: 34372558 PMCID: PMC8310243 DOI: 10.3390/v13071351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/03/2021] [Accepted: 07/08/2021] [Indexed: 11/17/2022] Open
Abstract
Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.
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30
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Hepatocellular cancer therapy in patients with HIV infection: Disparities in cancer care, trials enrolment, and cancer-related research. Transl Oncol 2021; 14:101153. [PMID: 34144349 PMCID: PMC8220238 DOI: 10.1016/j.tranon.2021.101153] [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] [Received: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
In the highly active antiretroviral therapy (HAART) era, hepatocellular carcinoma (HCC) is arising as a common late complication of human immunodeficiency virus (HIV) infection, with a great impact on morbidity and mortality. Though HIV infection alone may not be sufficient to promote hepatocarcinogenesis, the complex interaction of HIV with hepatitis is a main aspect influencing HCC morbidity and mortality. Data about sorafenib effectiveness and safety in HIV-infected patients are limited, particularly for patients who are on HAART. However, in properly selected subgroups, outcomes may be comparable to those of HIV-uninfected patients. Scarce data are available for those other systemic treatments, either tyrosine kinase inhibitors, as well as immune checkpoint inhibitors (ICIs), which have been added to our therapeutic armamentarium. This review examines the influence of HIV infection on HCC development and natural history, summarizes main data on systemic therapies, offers some insight into possible mechanisms of T cell exhaustion and reversal of HIV latency with ICIs and issues about clinical trials enrollment. Nowadays, routine exclusion of HIV-infected patients from clinical trial participation is totally inappropriate, since it leaves a number of patients deprived of life-prolonging therapies.
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31
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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells 2021; 10:cells10061332. [PMID: 34071188 PMCID: PMC8227136 DOI: 10.3390/cells10061332] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.
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32
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Guo L, Li H, Fan T, Ma Y, Wang L. Synergistic efficacy of curcumin and anti-programmed cell death-1 in hepatocellular carcinoma. Life Sci 2021; 279:119359. [PMID: 33753114 DOI: 10.1016/j.lfs.2021.119359] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/02/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) ranks near the top in the global list of malignancies causing cancer-related death. Recently, combination therapy has gained popularity in treating this cancer. We tried to investigate the efficacy of combined treatment with curcumin and anti-programmed cell death-1 (anti-PD-1) in HCC. Hep3B cells were treated with different concentrations of curcumin, followed by determination of Hep3B cell proliferation and programmed cell death ligand-1 (PD-L1) expression. Then, Hep3B cells were co-cultured with peripheral blood mononuclear cells (PBMCs), after which the Hep3B cell growth and immune activity were detected following treatment with curcumin and/or anti-PD-1. Besides, we investigated the effect of transforming growth factor beta 1 (TGF-β1) on lymphocyte activation and the interaction between E1A binding protein P300 (P300), histone acetylation, TGF-β1, and thrombin. Additionally, the synergistic role of curcumin and anti-PD-1 in mouse models of HCC was studied. Curcumin retarded Hep3B cell growth and reduced surface PD-L1 expression in Hep3B cells. After co-culture of Hep3B cells and PBMCs, curcumin had a synergistic effect with anti-PD-1 to slow Hep3B cell proliferation, activate lymphocytes, inhibit immune evasion, and down-regulate TGF-β1 expression. Functionally, curcumin inhibited thrombin to reduce P300-induced histone acetylation in the TGF-β1 promoter region, and anti-PD-1 suppressed binding of PD-1 and PD-L1 to promote immune activity; the combination of the two showed better in vitro anti-cancer effects. In vivo, curcumin combined with anti-PD-1 also lowered HCC growth rate and improved the tumor microenvironment. In conclusion, the combination of curcumin and anti-PD-1 is synergistically effective in the treatment of HCC treatment.
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Affiliation(s)
- Lei Guo
- Department of Infection, Qingdao No. 6 People's Hospital, Qingdao 266033, PR China
| | - Hongbo Li
- Department of Dermatology, Qingdao No. 6 People's Hospital, Qingdao 266033, PR China
| | - Tianli Fan
- Department of Infection, Qingdao No. 6 People's Hospital, Qingdao 266033, PR China
| | - Yanli Ma
- Department of Infection, Qingdao No. 6 People's Hospital, Qingdao 266033, PR China.
| | - Lili Wang
- Department of Hepatology, Qingdao No. 6 People's Hospital, Qingdao 266033, PR China.
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33
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Lee H, Da Silva IP, Palendira U, Scolyer RA, Long GV, Wilmott JS. Targeting NK Cells to Enhance Melanoma Response to Immunotherapies. Cancers (Basel) 2021; 13:cancers13061363. [PMID: 33802954 PMCID: PMC8002669 DOI: 10.3390/cancers13061363] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 12/23/2022] Open
Abstract
Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells.
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Affiliation(s)
- Hansol Lee
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
- Faculty of Medicine and Health Sciences, The University of Sydney, Sydney 2006, Australia
| | - Inês Pires Da Silva
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
| | - Umaimainthan Palendira
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
- Department of Infectious Diseases and Immunology, The Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Sydney 2006, Australia
| | - Richard A. Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
- Faculty of Medicine and Health Sciences, The University of Sydney, Sydney 2006, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney 2006, Australia
| | - Georgina V. Long
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
- Department of Medical Oncology, Royal North Shore Hospital and Mater Hospital, Sydney 2065, Australia
- Sydney Medical School, The University of Sydney, Sydney 2006, Australia
- Correspondence: ; Tel.: +61-2-9911-7336
| | - James S. Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney 2006, Australia; (H.L.); (I.P.D.S.); (U.P.); (R.A.S.); (J.S.W.)
- Faculty of Medicine and Health Sciences, The University of Sydney, Sydney 2006, Australia
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34
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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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35
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Shaw BI, Espinosa JR, Stempora L, Miller A, Adams B, Kirk AD. Functional Characteristics and Phenotypic Plasticity of CD57 +PD1 - CD4 T Cells and Their Relationship with Transplant Immunosuppression. THE JOURNAL OF IMMUNOLOGY 2021; 206:1668-1676. [PMID: 33597150 DOI: 10.4049/jimmunol.2000736] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 01/20/2021] [Indexed: 12/28/2022]
Abstract
Costimulation blockade (CoB)-based immunosuppression offers the promise of improved transplantation outcomes with reduced drug toxicity. However, it is hampered by early acute rejections, mediated at least in part by differentiated, CoB-resistant T cells, such as CD57+PD1- CD4 T cells. In this study, we characterize these cells pretransplant, determine their fate posttransplant, and examine their proliferative capacity in vitro in humans. Our studies show that CD57+PD1- CD4 T cells are correlated with increasing age and CMV infection pretransplant, and persist for up to 1 y posttransplant. These cells are replication incompetent alone but proliferated in the presence of unsorted PBMCs in a contact-independent manner. When stimulated, cells sorted by CD57/PD1 status upregulate markers of activation with proliferation. Up to 85% of CD57+PD1- cells change expression of CD57/PD1 with stimulation, typically, upregulating PD1 and downregulating CD57. PD1 upregulation is accentuated in the presence of rapamycin but prevented by tacrolimus. These data support a general theory of CoB-resistant cells as Ag-experienced, costimulation-independent cells and suggest a mechanism for the synergy of belatacept and rapamycin, with increased expression of the activation marker PD1 potentiating exhaustion of CoB-resistant cells.
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Affiliation(s)
- Brian I Shaw
- Department of Surgery, Duke University, Durham, NC 27710
| | | | - Linda Stempora
- Department of Surgery, Duke University, Durham, NC 27710
| | - Allison Miller
- Department of Surgery, Duke University, Durham, NC 27710
| | - Bartley Adams
- Department of Surgery, Duke University, Durham, NC 27710
| | - Allan D Kirk
- Department of Surgery, Duke University, Durham, NC 27710
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36
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Wu D, Hu S, Chen G, Chen L, Liu J, Chen W, Lv Y, Chen X, Lin S, Wu F. Association of hepatitis C infection and risk of kidney cancer: A systematic review and meta-analysis of observational studies. J Viral Hepat 2021; 28:226-235. [PMID: 33141502 DOI: 10.1111/jvh.13434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Although some epidemiological studies have investigated the association between Hepatitis C virus (HCV) infection and the development of kidney cancer, the results are far from consistent. We conducted a systematic review and meta-analysis of observational studies to determine the association. PubMed, EMBASE and Cochrane database were searched from 1 January 1975 to 7 January 2020. Study selection, data extraction and bias assessment (using the Newcastle-Ottawa scale) were performed independently by 2 authors. Pooled odds ratios (ORs) with corresponding confidence intervals (CIs) were calculated using a random-effects model. In all, 16 studies (11 cohort studies and 5 case-control studies) involving a total of 391,071 HCV patients and 38,333,839 non-HCV controls were included. The overall analysis showed a 47% higher risk to develop kidney cancer among the patients with HCV infection (pooled OR 1.47; 95% CI 1.14-1.91), despite significant heterogeneity (I2 = 87.6%). The multivariable meta-regression showed that study design, age, sample size and HIV co-infection were significant sources of variance, and totally accounted for 82% of the I2 . The risk of KC in HCV patients was further increased in studies without HCV/HBV- and HCV/HIV- co-infection (pooled OR 1.66; 95%CI 1.23-2.24). Multiple sensitivity analyses did not change the significant association. The present meta-analysis indicated that HCV-infected patients have a significantly higher risk of developing kidney cancer. Our results highlighted the rationale for improved renal surveillance in HCV patients for the early diagnosis of kidney cancer. Further investigations for the mechanisms underlying HCV-induced kidney cancer are warranted.
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Affiliation(s)
- Di Wu
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Shiping Hu
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Guozi Chen
- Department of Urology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Longjiao Chen
- Department of Urology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Jian Liu
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Wenlin Chen
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Youwen Lv
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Xiaoni Chen
- Department of Urology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Shan Lin
- Department of Urology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
| | - Fenfang Wu
- Department of Hepatology, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China
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Sung PS, Shin EC. Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection. J Clin Med 2021; 10:E221. [PMID: 33435135 PMCID: PMC7827927 DOI: 10.3390/jcm10020221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/08/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.
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Affiliation(s)
- Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
- The Catholic Liver Research Center, The Catholic University of Korea, Seoul 06591, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- The Center for Epidemic Preparedness, KAIST Institute, Daejeon 34141, Korea
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38
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Chua C, Salimzadeh L, Gehring AJ. Immunopathogenesis of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:73-97. [DOI: 10.1007/978-981-16-3615-8_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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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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40
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Smith S, Honegger JR, Walker C. T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a036954. [PMID: 32205413 PMCID: PMC7778213 DOI: 10.1101/cshperspect.a036954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4+ and CD8+ T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an era of highly effective antiviral therapy for chronic hepatitis C. First, the characteristics of successful T-cell responses that promote resolution of HCV infection are considered, as they will underpin development of vaccines that prevent HCV persistence. Second, defects in T-cell immunity that facilitate HCV persistence and whether they are reversed after antiviral cure to provide protection from reinfection are also addressed.
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Affiliation(s)
- Stephanie Smith
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Jonathan R. Honegger
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Christopher Walker
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
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De Re V, Tornesello ML, De Zorzi M, Caggiari L, Pezzuto F, Leone P, Racanelli V, Lauletta G, Zanussi S, Repetto O, Gragnani L, Rossi FM, Dolcetti R, Zignego AL, Buonaguro FM, Steffan A. PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus-related diseases. Liver Int 2021; 41:133-149. [PMID: 32937024 PMCID: PMC7839592 DOI: 10.1111/liv.14667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 08/11/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV-positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine the association of these genes with patient's outcome. METHODS Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD-1 and its ligand PD-L1. RESULTS The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV-related diseases than blood donors (P < .0001). Patients expressing the IFNλ4 variant with one amino acid change that reduces IFNλ4 secretion was found increased in frequency in HCV-related diseases compared to HCC PDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD-1.3 A or the PD-1.7 G allele (P = .0025 and P = .0167). Linkage disequilibrium (LD) between PD-1.3 and IFNL4 was found in patients with mixed cryoglobulinaemia (MC) only (LD = 0 in HCC; LD = 72 in MC). PBMCs of MC patients expressed low levels of PD-L1 in CD19+IgM+B cells and of PD-1 in CD4+T cells suggesting the involvement of regulatory B cell-T cell interaction to the pathogenesis of MC. CONCLUSION Collectively, our data indicate an important contribution of IFNλ4 expression to the development of HCV-related HCC and an epistatic contribution of IFNL4 and PDCD1 in MC. LAY SUMMARY Studies of IFNL4 and PDCD1 genes are helpful to better understand the role of host genetic factors and immune antigens influencing the outcome of HCV-related diseases. Our data support an association between the expression of IFNλ4, which prevents the expression of IFNλ3, with all the different HCV-related diseases studied, and besides, evidence that a higher IFNλ4 expression is associated with hepatocellular at a younger age. The expression pattern of low PD-L1 on B cells and high PD-1 on CD4+T-cells in patients with HCV-positive cryoglobulinaemia suggests a critical role of the PD-1/PD-L1 signaling in modulating B cell-T cell interaction in this lymphoproliferative disease.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
| | - Maria Lina Tornesello
- Molecular biologyviral oncology Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"NapoliItaly
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
| | - Laura Caggiari
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
| | - Francesca Pezzuto
- Molecular biologyviral oncology Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"NapoliItaly
| | - Patrizia Leone
- Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBariItaly
| | - Vito Racanelli
- Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBariItaly
| | - Gianfranco Lauletta
- Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBariItaly
| | - Stefania Zanussi
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
| | - Ombretta Repetto
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
| | - Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE)Internal Medicine and Liver UnitDepartment of Experimental and Clinical MedicineCareggi University Hospital, Florence, ItalyFlorenceItaly
| | - Francesca Maria Rossi
- Clinical and Experimental Onco‐Hematology UnitCentro di Riferimento Oncologico (CRO) IRCCSAviano (PN)Italy
| | - Riccardo Dolcetti
- The University of Queensland Diamantina InstituteTranslational Research InstituteBrisbaneAustralia
| | - Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE)Internal Medicine and Liver UnitDepartment of Experimental and Clinical MedicineCareggi University Hospital, Florence, ItalyFlorenceItaly
| | - Franco M. Buonaguro
- Molecular biologyviral oncology Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"NapoliItaly
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers/Bioproteomic facilityDepartment of Translational ResearchCentro di Riferimento Oncologico (CRO) IRCCSCancer InstituteAvianoItaly
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42
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Lineburg KE, Srihari S, Altaf M, Swaminathan S, Panikkar A, Raju J, Crooks P, Ambalathingal GR, Martins JP, Matthews KK, Neller MA, Khanna R, Smith C. Rapid detection of SARS-CoV-2-specific memory T-cell immunity in recovered COVID-19 cases. Clin Transl Immunology 2020; 9:e1219. [PMID: 33312565 PMCID: PMC7720530 DOI: 10.1002/cti2.1219] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/14/2020] [Accepted: 11/05/2020] [Indexed: 12/31/2022] Open
Abstract
Objectives There is emerging evidence that SARS‐CoV‐2‐specific memory T‐cell responses are likely to provide critical long‐term protection against COVID‐19. Strategies to rapidly assess T‐cell responses are therefore likely to be important for assessing immunity in the global population. Methods Here, we have developed a rapid immune‐monitoring strategy to assess virus‐specific memory T‐cell responses in the peripheral blood of COVID‐19 convalescent individuals. We validated SARS‐CoV‐2‐specific memory T‐cell responses detected in whole blood using in vitro expansion with SARS‐CoV‐2 proteins. Results T‐cell immunity characterised by the production of IFN‐γ and IL‐2 could be consistently detected in the whole blood of recovered participants. T cells predominantly recognised structural SARS‐CoV‐2 proteins. In vitro expansion demonstrated that while CD8+ T cells recognised nucleocapsid protein, spike protein and ORF3a, CD4+ T cells more broadly targeted multiple SARS‐CoV‐2 proteins. Conclusion These observations provide a timely monitoring approach for identifying SARS‐CoV‐2 cellular immunity and may serve as a diagnostic for the stratification of risk in immunocompromised and other at‐risk individuals.
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Affiliation(s)
- Katie E Lineburg
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Sriganesh Srihari
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Mohammed Altaf
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
| | - Srividhya Swaminathan
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
| | - Archana Panikkar
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Jyothy Raju
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Pauline Crooks
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - George R Ambalathingal
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Jose Paulo Martins
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Katherine K Matthews
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Michelle A Neller
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia
| | - Rajiv Khanna
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
| | - Corey Smith
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory Department of Immunology QIMR Berghofer Medical Research Institute Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
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43
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Lim HK, Jeffrey GP, Ramm GA, Soekmadji C. Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles. Front Cell Infect Microbiol 2020; 10:587628. [PMID: 33240824 PMCID: PMC7683521 DOI: 10.3389/fcimb.2020.587628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.
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Affiliation(s)
- Hong Kiat Lim
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gary P Jeffrey
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.,Sir Charles Gairdner Hospital, Nedlands, Hepatology Department and Liver Transplant Service, Perth, WA, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Carolina Soekmadji
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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44
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Garrido A, Djouder N. Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma. Trends Cancer 2020; 7:29-36. [PMID: 32917550 DOI: 10.1016/j.trecan.2020.08.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/30/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023]
Abstract
The liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.
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Affiliation(s)
- Amanda Garrido
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
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45
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Kemming J, Thimme R, Neumann-Haefelin C. Adaptive Immune Response against Hepatitis C Virus. Int J Mol Sci 2020; 21:ijms21165644. [PMID: 32781731 PMCID: PMC7460648 DOI: 10.3390/ijms21165644] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/18/2022] Open
Abstract
A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.
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Affiliation(s)
- Janine Kemming
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg im Breisgau, Germany
| | - Robert Thimme
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Correspondence: ; Tel.: +49-761-270-32800
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Vigano S, Bobisse S, Coukos G, Perreau M, Harari A. Cancer and HIV-1 Infection: Patterns of Chronic Antigen Exposure. Front Immunol 2020; 11:1350. [PMID: 32714330 PMCID: PMC7344140 DOI: 10.3389/fimmu.2020.01350] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/27/2020] [Indexed: 12/14/2022] Open
Abstract
The main role of the human immune system is to eliminate cells presenting foreign antigens and abnormal patterns, while maintaining self-tolerance. However, when facing highly variable pathogens or antigens very similar to self-antigens, this system can fail in completely eliminating the anomalies, leading to the establishment of chronic pathologies. Prototypical examples of immune system defeat are cancer and Human Immunodeficiency Virus-1 (HIV-1) infection. In both conditions, the immune system is persistently exposed to antigens leading to systemic inflammation, lack of generation of long-term memory and exhaustion of effector cells. This triggers a negative feedback loop where effector cells are unable to resolve the pathology and cannot be replaced due to the lack of a pool of undifferentiated, self-renewing memory T cells. In addition, in an attempt to reduce tissue damage due to chronic inflammation, antigen presenting cells and myeloid components of the immune system activate systemic regulatory and tolerogenic programs. Beside these homologies shared between cancer and HIV-1 infection, the immune system can be shaped differently depending on the type and distribution of the eliciting antigens with ultimate consequences at the phenotypic and functional level of immune exhaustion. T cell differentiation, functionality, cytotoxic potential and proliferation reserve, immune-cell polarization, upregulation of negative regulators (immune checkpoint molecules) are indeed directly linked to the quantitative and qualitative differences in priming and recalling conditions. Better understanding of distinct mechanisms and functional consequences underlying disease-specific immune cell dysfunction will contribute to further improve and personalize immunotherapy. In the present review, we describe relevant players of immune cell exhaustion in cancer and HIV-1 infection, and enumerate the best-defined hallmarks of T cell dysfunction. Moreover, we highlight shared and divergent aspects of T cell exhaustion and T cell activation to the best of current knowledge.
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Affiliation(s)
- Selena Vigano
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Sara Bobisse
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - George Coukos
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Matthieu Perreau
- Service of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland
| | - Alexandre Harari
- Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland
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Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation. PLoS Pathog 2020; 16:e1008555. [PMID: 32579593 PMCID: PMC7340326 DOI: 10.1371/journal.ppat.1008555] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 07/07/2020] [Accepted: 04/15/2020] [Indexed: 12/23/2022] Open
Abstract
Exhaustion is a dysfunctional state of cytotoxic CD8+ T cells (CTL) observed in chronic infection and cancer. Current in vivo models of CTL exhaustion using chronic viral infections or cancer yield very few exhausted CTL, limiting the analysis that can be done on these cells. Establishing an in vitro system that rapidly induces CTL exhaustion would therefore greatly facilitate the study of this phenotype, identify the truly exhaustion-associated changes and allow the testing of novel approaches to reverse or prevent exhaustion. Here we show that repeat stimulation of purified TCR transgenic OT-I CTL with their specific peptide induces all the functional (reduced cytokine production and polyfunctionality, decreased in vivo expansion capacity) and phenotypic (increased inhibitory receptors expression and transcription factor changes) characteristics of exhaustion. Importantly, in vitro exhausted cells shared the transcriptomic characteristics of the gold standard of exhaustion, CTL from LCMV cl13 infections. Gene expression of both in vitro and in vivo exhausted CTL was distinct from T cell anergy. Using this system, we show that Tcf7 promoter DNA methylation contributes to TCF1 downregulation in exhausted CTL. Thus this novel in vitro system can be used to identify genes and signaling pathways involved in exhaustion and will facilitate the screening of reagents that prevent/reverse CTL exhaustion.
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Priming of Antiviral CD8 T Cells without Effector Function by a Persistently Replicating Hepatitis C-Like Virus. J Virol 2020; 94:JVI.00035-20. [PMID: 32102885 DOI: 10.1128/jvi.00035-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 02/06/2020] [Indexed: 12/14/2022] Open
Abstract
Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.
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Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment. J Hepatocell Carcinoma 2020; 7:45-76. [PMID: 32346535 PMCID: PMC7167284 DOI: 10.2147/jhc.s221187] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFN-α) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
- Department of Medicine, Division of Gastroenterology, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA70112, USA
| | - Kyle E Widmer
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
| | - Leela Nayak
- Southeast Louisiana Veterans Health Care System, New Orleans, LA70119, USA
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50
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Marcel N, Hedrick SM. A key control point in the T cell response to chronic infection and neoplasia: FOXO1. Curr Opin Immunol 2020; 63:51-60. [PMID: 32135399 DOI: 10.1016/j.coi.2020.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/29/2020] [Accepted: 02/01/2020] [Indexed: 12/26/2022]
Abstract
T cells able to control neoplasia or chronic infections display a signature gene expression profile similar or identical to that of central memory T cells. These cells have qualities of self-renewal and a plasticity that allow them to repeatedly undergo activation (growth, proliferation, and differentiation), followed by quiescence. It is these qualities that define the ability of T cells to establish an equilibrium with chronic infectious agents, and also preserve the ability of T cells to be re-activated (by checkpoint therapy) in response to malignant cancers. Here we describe distinctions between the forms of inhibition mediated by tumors and persistent viruses, we review the properties of T cells associated with long-term immunity, and we identify the transcription factor, FOXO1, as the control point for a program of gene expression that allows CD8+ T cells to undergo serial reactivation and self-renewal.
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Affiliation(s)
- Nimi Marcel
- Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, TATA Institute for Genetics and Society, University of California, San Diego, La Jolla, CA 92093-0377, United States
| | - Stephen M Hedrick
- Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, TATA Institute for Genetics and Society, University of California, San Diego, La Jolla, CA 92093-0377, United States.
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