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Xu C, Cao K, Ma A, Zheng M, Xu Y, Tang L. KLRG1 expression induces functional exhaustion of NK cells in colorectal cancer patients. Cancer Immunol Immunother 2025; 74:203. [PMID: 40372495 PMCID: PMC12081801 DOI: 10.1007/s00262-025-04059-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/14/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Natural killer (NK) cells are a subset of innate lymphoid cells that possess cytotoxic properties, playing a pivotal role in immune surveillance against tumor cells. However, it remains unclear whether there are any alterations in the quantity and functional status of NK cells in colorectal cancer (CRC). METHODS In this study, we collected peripheral blood samples from both CRC patients and age- and sex-matched healthy controls (HCs). The distribution characteristics, phenotypic changes, functional status, apoptosis susceptibility, and proliferative capacity of circulating NK cells were detected and analyzed by flow cytometry. An in vitro study was performed to investigate the blocking effect of KLRG1 antibody on peripheral blood NK cells in CRC patients. RESULTS The frequency and absolute number of circulating NK cells were significantly decreased in CRC patients compared to those in HCs. Meanwhile, the function of NK cells from CRC patients was compromised, as shown by the reduced production of IFN-γ, TNF-α, and CD107a, with this impairment becoming increasingly significant as neural invasion progressed and tumor invasion advanced. We further found that the expression of activating receptors NKp30 and NKp46 were reduced, while the expression of inhibitory receptor KLRG1 was remarkably increased. The increased proportion of KLRG1 on NK cells was associated with CRC progression, and KLRG1+ NK cells showed impaired production of IFN-γ, TNF-α, and CD107a and were more susceptible to apoptosis. Importantly, blockade of the KLRG1 pathway could restore the cytokine production and degranulation ability of NK cells from CRC patients. CONCLUSIONS The present study demonstrates that NK cells in CRC patients exhibit functional exhaustion, and KLRG1 blockade restores the effector function of NK cells, indicating that targeting KLRG1 represents a promising strategy for immunotherapy in patients with CRC.
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Affiliation(s)
- Cairui Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Kangli Cao
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Along Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Meijuan Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China
| | - Ling Tang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei, Anhui, People's Republic of China.
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2
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Qiu Z, Li Z, Zhang C, Zhao Q, Liu Z, Cheng Q, Zhang J, Lin A, Luo P. NK Cell Senescence in Cancer: From Molecular Mechanisms to Therapeutic Opportunities. Aging Dis 2025:AD.2025.0053. [PMID: 40249925 DOI: 10.14336/ad.2025.0053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2025] [Accepted: 03/13/2025] [Indexed: 04/20/2025] Open
Abstract
P Natural killer (NK) cells function as crucial effectors in the innate immune response against tumors. Nevertheless, NK cell senescence, characterized by phenotypic and functional changes, substantially compromises their antitumor immune response. This review provides a comprehensive summary of the molecular mechanisms governing NK cell senescence and its implications for cancer immunotherapy. We propose a refined definition of NK cell senescence based on distinct biomarkers, including elevated CD57 expression, reduced cytotoxicity, and altered cytokine secretion. Moreover, we investigate the complex interactions between the tumor microenvironment (TME) and NK cell senescence, highlighting the influence of chronic inflammation, immunosuppressive cytokines, and persistent tumor antigenic stimulation. Additionally, this review underscores the potential utility of senescent NK cells as biomarkers for assessing antitumor efficacy and examines the adverse effects of NK cell senescence on cancer immunotherapy. Lastly, we summarize current approaches to mitigate NK cell senescence, such as gene editing techniques and cytokine modulation, which may enhance the efficacy of NK cell-based immunotherapies. By establishing a comprehensive framework for understanding NK cell senescence within the TME, this review aims to guide future research and the development of innovative therapeutic strategies targeting senescent NK cells to improve cancer immunotherapy outcomes.
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Affiliation(s)
- Zilin Qiu
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Zhengrui Li
- Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Big data analysis and mining application for precise diagnosis and treatment of gastric cancer Hebei Provincial Engineering Research Center, Shijiazhuang 050011, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Anqi Lin
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Peng Luo
- Donghai County People's Hospital - Jiangnan University Smart Healthcare Joint Laboratory, Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University), Lianyungang, 222000, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
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Galvani RGA, Rojas A, Matuck BF, Rupp BT, Kumar N, Huynh K, de Biagi CAO, Liu J, Sheth S, Krol JMM, Maracaja-Coutinho V, Byrd KM, Severino P. The Single-Cell Landscape of Peripheral and Tumor-infiltrating Immune Cells in HPV- HNSCC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.14.632928. [PMID: 39868329 PMCID: PMC11760799 DOI: 10.1101/2025.01.14.632928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HPV-negative HNSCC, which arises in the upper airway mucosa, is particularly aggressive, with nearly half of patients succumbing to the disease within five years and limited response to immune checkpoint inhibitors compared to other cancers. There is a need to further explore the complex immune landscape in HPV-negative HNSCC to identify potential therapeutic targets. Here, we integrated two single-cell RNA sequencing datasets from 29 samples and nearly 300,000 immune cells to investigate immune cell dynamics across tumor progression and lymph node metastasis. Notable shifts toward adaptative immune cell populations were observed in the 14 distinct HNSCC-associated peripheral blood mononuclear (PBMCs) and 21 tumor-infiltrating immune cells (TICs) considering disease stages. All PBMCs and TICs revealed unique molecular signatures correlating with lymph node involvement; however, broadly, TICs increased ligand expression among effector cytokines, growth factors, and interferon-related genes. Pathway analysis comparing PBMCs and TICs further confirmed active cell signaling among Monocyte-Macrophage, Dendritic cell, Natural Killer (NK), and T cell populations. Receptor-ligand analysis revealed significant communication patterns shifts among TICs, between CD8+ T cells and NK cells, showing heightened immunosuppressive signaling that correlated with disease progression. In locally invasive HPV-negative HNSCC samples, highly multiplexed immunofluorescence assays highlighted peri-tumoral clustering of exhausted CD8+ T and NK cells, alongside their exclusion from intra-tumoral niches. These findings emphasize cytotoxic immune cells as valuable biomarkers and therapeutic targets, shedding light on the mechanisms by which the HNSCC sustainably evades immune responses.
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Affiliation(s)
- Rômulo Gonçalves Agostinho Galvani
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Brazil
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil
| | | | - Bruno F. Matuck
- Department of Innovation & Technology Research, ADA Science & Research Institute, Gaithersburg, MD, USA
- Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, USA
| | - Brittany T. Rupp
- Department of Innovation & Technology Research, ADA Science & Research Institute, Gaithersburg, MD, USA
- Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, USA
| | - Nikhil Kumar
- Department of Innovation & Technology Research, ADA Science & Research Institute, Gaithersburg, MD, USA
| | - Khoa Huynh
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Jinze Liu
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA
| | - Siddharth Sheth
- Division of Medical Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | | | - Kevin Matthew Byrd
- Department of Innovation & Technology Research, ADA Science & Research Institute, Gaithersburg, MD, USA
- Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, USA
| | - Patricia Severino
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Brazil
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Zhu YX, Li ZY, Yu ZL, Lu YT, Liu JX, Chen JR, Xie ZZ. The underlying mechanism and therapeutic potential of IFNs in viral-associated cancers. Life Sci 2025; 361:123301. [PMID: 39675548 DOI: 10.1016/j.lfs.2024.123301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024]
Abstract
Interferons (IFNs) are a diverse family of cytokines secreted by various cells, including immune cells, fibroblasts, and certain viral-parasitic cells. They are classified into three types and encompass 21 subtypes based on their sources and properties. The regulatory functions of IFNs closely involve cell surface receptors and several signal transduction pathways. Initially investigated for their antiviral properties, IFNs have shown promise in combating cancer-associated viruses, making them a potent therapeutic approach. Most IFNs have been identified for their role in inhibiting cancer; however, they have also demonstrated cancer-promoting effects under specific conditions. These mechanisms primarily rely on immune regulation and cytotoxic effects, significantly impacting cancer progression. Despite widespread use of IFN-based therapies in viral-related cancers, ongoing research aims to develop more effective treatments. This review synthesizes the signal transduction pathways and regulatory capabilities of IFNs, highlighting their connections with viruses, cancers, and emerging clinical treatments.
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Affiliation(s)
- Yu-Xin Zhu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Zi-Yi Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Zi-Lu Yu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Yu-Tong Lu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Jia-Xiang Liu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Jian-Rui Chen
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330031, PR China
| | - Zhen-Zhen Xie
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330031, PR China.
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Rodríguez-Martín M, Pérez-Sanz F, Zambrano C, Luján J, Ryden M, Scheer FAJL, Garaulet M. Circadian transcriptome oscillations in human adipose tissue depend on napping status and link to metabolic and inflammatory pathways. Sleep 2024; 47:zsae160. [PMID: 38995117 PMCID: PMC11543616 DOI: 10.1093/sleep/zsae160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/26/2024] [Indexed: 07/13/2024] Open
Abstract
STUDY OBJECTIVES Napping is a common habit in many countries. Nevertheless, studies about the chronic effects of napping on obesity are contradictory, and the molecular link between napping and metabolic alterations has yet to be studied. We aim to identify molecular mechanisms in adipose tissue (AT) that may connect napping and abdominal obesity. METHODS In this cross-sectional study, we extracted the RNA repeatedly across 24 hours from cultured AT explants and performed RNA sequencing. Circadian rhythms were analyzed using six consecutive time points across 24 hours. We also assessed global gene expression in each group (nappers vs. non-nappers). RESULTS With napping, there was an 88% decrease in the number of rhythmic genes compared to that in non-nappers, a reduction in rhythm amplitudes of 29%, and significant phase changes from a coherent unimodal acrophase in non-nappers, towards a scattered and bimodal acrophase in nappers. Those genes that lost rhythmicity with napping were mainly involved in pathways of glucose and lipid metabolism, and of the circadian clock. Additionally, we found differential global gene expression between nappers and non-nappers with 34 genes down- and 32 genes upregulated in nappers. The top upregulated gene (IER3) and top down-regulated pseudogene (VDAC2P2) in nappers have been previously shown to be involved in inflammation. CONCLUSIONS These new findings have implications for our understanding of napping's relationship with obesity and metabolic disorders.
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Affiliation(s)
- María Rodríguez-Martín
- Department of Physiology, Regional Campus of International Excellence, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca-Universidad de Murcia (UMU), University Clinical Hospital, Murcia, Spain
| | - Fernando Pérez-Sanz
- Biomedical Research Institute of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca-Universidad de Murcia (UMU), University Clinical Hospital, Murcia, Spain
| | - Carolina Zambrano
- Department of Physiology, Regional Campus of International Excellence, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca-Universidad de Murcia (UMU), University Clinical Hospital, Murcia, Spain
| | - Juan Luján
- General Surgery Service, Hospital Quirón salud, Murcia, Spain
| | - Mikael Ryden
- Endocrinology Unit, Department of Medicine Huddinge (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Frank A J L Scheer
- Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Marta Garaulet
- Department of Physiology, Regional Campus of International Excellence, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca-Universidad de Murcia (UMU), University Clinical Hospital, Murcia, Spain
- Endocrinology Unit, Department of Medicine Huddinge (H7), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, Boston, MA, USA
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6
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Rubino G, Yörük E. Immunosenescence, immunotolerance and rejection: clinical aspects in solid organ transplantation. Transpl Immunol 2024; 86:102068. [PMID: 38844001 DOI: 10.1016/j.trim.2024.102068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 05/27/2024] [Accepted: 06/01/2024] [Indexed: 07/21/2024]
Abstract
As a consequence of increased lifespan and rising number of elderly individuals developing end-stage organ disease, the higher demand for organs along with a growing availability for organs from older donors pose new challenges for transplantation. During aging, dynamic adaptations in the functionality and structure of the biological systems occur. Consistently, immunosenescence (IS) accounts for polydysfunctions within the lymphocyte subsets, and the onset of a basal but persistent systemic inflammation characterized by elevated levels of pro-inflammatory mediators. There is an emerging consensus about a causative link between such hallmarks and increased susceptibility to morbidities and mortality, however the role of IS in solid organ transplantation (SOT) remains loosely addressed. Dissecting the immune-architecture of immunologically-privileged sites may prompt novel insights to extend allograft survival. A deeper comprehension of IS in SOT might unveil key standpoints for the clinical management of transplanted patients.
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Affiliation(s)
- Graziella Rubino
- University Hospital Tübingen, Department of Tropical Medicine, Wilhelmstraße 27, 72074 Tübingen, Germany; Institute for Transfusion Medicine, University Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, 89081 Ulm, Germany.
| | - Efdal Yörük
- Berit Klinik, Gastrointestinal Center, Florastrasse 1, 9403 Goldach, Switzerland; University Hospital Tübingen, Department of Ophthalmology, Elfriede-Alhorn-Straße 7, 72076 Tübingen, Germany
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7
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Zhang Y, Chen S, Tang X, Peng Y, Jiang T, Zhang X, Li J, Liu Y, Yang Z. The role of KLRG1: a novel biomarker and new therapeutic target. Cell Commun Signal 2024; 22:337. [PMID: 38898461 PMCID: PMC11186184 DOI: 10.1186/s12964-024-01714-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 06/13/2024] [Indexed: 06/21/2024] Open
Abstract
Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.
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Affiliation(s)
- Yakun Zhang
- School of Medicine, Chongqing University, Chongqing, 400030, China
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Shuang Chen
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Xinyi Tang
- School of Medicine, Chongqing University, Chongqing, 400030, China
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yu Peng
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Tingting Jiang
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Xiaomei Zhang
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Jun Li
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yao Liu
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China.
| | - Zailin Yang
- Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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8
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Anderko RR, DePuyt AE, Bronson R, Bullotta AC, Aga E, Bosch RJ, Jones RB, Eron JJ, Mellors JW, Gandhi RT, McMahon DK, Macatangay BJ, Rinaldo CR, Mailliard RB. Persistence of a Skewed Repertoire of NK Cells in People with HIV-1 on Long-Term Antiretroviral Therapy. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1564-1578. [PMID: 38551350 PMCID: PMC11073922 DOI: 10.4049/jimmunol.2300672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/11/2024] [Indexed: 04/05/2024]
Abstract
HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.
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Affiliation(s)
- Renee R. Anderko
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Allison E. DePuyt
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Rhianna Bronson
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Arlene C. Bullotta
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Evgenia Aga
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ronald J. Bosch
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - R. Brad Jones
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Joseph J. Eron
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - John W. Mellors
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Rajesh T. Gandhi
- Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Deborah K. McMahon
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Bernard J. Macatangay
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Charles R. Rinaldo
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Robbie B. Mailliard
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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9
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Spiteri AG, Wishart CL, Pinget GV, Purohit SK, Macia L, King NJ, Niewold P. NK cell profiling in West Nile virus encephalitis reveals potential metabolic basis for functional inhibition. Immunol Cell Biol 2024; 102:280-291. [PMID: 38421112 DOI: 10.1111/imcb.12739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 02/09/2024] [Accepted: 02/09/2024] [Indexed: 03/02/2024]
Abstract
Natural killer (NK) cells are cytotoxic lymphocytes important for viral defense. West Nile virus (WNV) infection of the central nervous system (CNS) causes marked recruitment of bone marrow (BM)-derived monocytes, T cells and NK cells, resulting in severe neuroinflammation and brain damage. Despite substantial numbers of NK cells in the CNS, their function and phenotype remain largely unexplored. Here, we demonstrate that NK cells mature from the BM to the brain, upregulate inhibitory receptors and show reduced cytokine production and degranulation, likely due to the increased expression of the inhibitory NK cell molecule, MHC-I. Intriguingly, this correlated with a reduction in metabolism associated with cytotoxicity in brain-infiltrating NK cells. Importantly, the degranulation and killing capability were restored in NK cells isolated from WNV-infected tissue, suggesting that WNV-induced NK cell inhibition occurs in the CNS. Overall, this work identifies a potential link between MHC-I inhibition of NK cells and metabolic reduction of their cytotoxicity during infection.
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Affiliation(s)
- Alanna G Spiteri
- Viral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Claire L Wishart
- Viral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Gabriela V Pinget
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Shivam K Purohit
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Laurence Macia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Sydney Cytometry, The University of Sydney and Centenary Institute, Sydney, NSW, Australia
| | - Nicholas Jc King
- Viral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Sydney Cytometry, The University of Sydney and Centenary Institute, Sydney, NSW, Australia
- The University of Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, NSW, Australia
- The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, Australia
| | - Paula Niewold
- Viral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands
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10
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Reggiani F, Talarico G, Gobbi G, Sauta E, Torricelli F, Manicardi V, Zanetti E, Orecchioni S, Falvo P, Piana S, Lococo F, Paci M, Bertolini F, Ciarrocchi A, Sancisi V. BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3. Nat Commun 2024; 15:2567. [PMID: 38519469 PMCID: PMC10960013 DOI: 10.1038/s41467-024-46778-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 03/11/2024] [Indexed: 03/25/2024] Open
Abstract
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.
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Affiliation(s)
- Francesca Reggiani
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
| | - Giovanna Talarico
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Giulia Gobbi
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elisabetta Sauta
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Federica Torricelli
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Veronica Manicardi
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Eleonora Zanetti
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Biobank, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Stefania Orecchioni
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Paolo Falvo
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Simonetta Piana
- Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Biobank, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Filippo Lococo
- Università Cattolica del Sacro Cuore, Rome, Italy
- Department of General Thoracic Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Massimiliano Paci
- Thoracic Surgery Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Francesco Bertolini
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy
- Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Alessia Ciarrocchi
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Valentina Sancisi
- Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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11
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Martyshkina YS, Tereshchenko VP, Bogdanova DA, Rybtsov SA. Reliable Hallmarks and Biomarkers of Senescent Lymphocytes. Int J Mol Sci 2023; 24:15653. [PMID: 37958640 PMCID: PMC10647376 DOI: 10.3390/ijms242115653] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
The phenomenon of accumulation of senescent adaptive immunity cells in the elderly is attracting attention due to the increasing risk of global epidemics and aging of the global population. Elderly people are predisposed to various infectious and age-related diseases and are at higher risk of vaccination failure. The accumulation of senescent cells increases age-related background inflammation, "Inflammaging", causing lymphocyte exhaustion and cardiovascular, neurodegenerative, autoimmune and cancer diseases. Here, we present a comprehensive contemporary review of the mechanisms and phenotype of senescence in the adaptive immune system. Although modern research has not yet identified specific markers of aging lymphocytes, several sets of markers facilitate the separation of the aging population based on normal memory and exhausted cells for further genetic and functional analysis. The reasons for the higher predisposition of CD8+ T-lymphocytes to senescence compared to the CD4+ population are also discussed. We point out approaches for senescent-lymphocyte-targeting markers using small molecules (senolytics), antibodies and immunization against senescent cells. The suppression of immune senescence is the most relevant area of research aimed at developing anti-aging and anti-cancer therapy for prolonging the lifespan of the global population.
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Affiliation(s)
- Yuliya S. Martyshkina
- Division of Immunobiology and Biomedicine, Center for Genetics and Life Sciences, Sirius University of Science and Technology, Olimpiyskiy Ave. b.1, Sirius 354340, Krasnodar Region, Russia; (Y.S.M.)
| | - Valeriy P. Tereshchenko
- Resource Center for Cell Technology and Immunology, Sirius University of Science and Technology, Olimpiyskiy Ave. b.1, Sirius 354340, Krasnodar Region, Russia
| | - Daria A. Bogdanova
- Division of Immunobiology and Biomedicine, Center for Genetics and Life Sciences, Sirius University of Science and Technology, Olimpiyskiy Ave. b.1, Sirius 354340, Krasnodar Region, Russia; (Y.S.M.)
| | - Stanislav A. Rybtsov
- Resource Center for Cell Technology and Immunology, Sirius University of Science and Technology, Olimpiyskiy Ave. b.1, Sirius 354340, Krasnodar Region, Russia
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12
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Astorga-Gamaza A, Perea D, Sanchez-Gaona N, Calvet-Mirabent M, Gallego-Cortés A, Grau-Expósito J, Sanchez-Cerrillo I, Rey J, Castellví J, Curran A, Burgos J, Navarro J, Suanzes P, Falcó V, Genescà M, Martín-Gayo E, Buzon MJ. KLRG1 expression on natural killer cells is associated with HIV persistence, and its targeting promotes the reduction of the viral reservoir. Cell Rep Med 2023; 4:101202. [PMID: 37741278 PMCID: PMC10591043 DOI: 10.1016/j.xcrm.2023.101202] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/25/2023] [Accepted: 08/29/2023] [Indexed: 09/25/2023]
Abstract
Human immunodeficiency virus (HIV) infection induces immunological dysfunction, which limits the elimination of HIV-infected cells during treated infection. Identifying and targeting dysfunctional immune cells might help accelerate the purging of the persistent viral reservoir. Here, we show that chronic HIV infection increases natural killer (NK) cell populations expressing the negative immune regulator KLRG1, both in peripheral blood and lymph nodes. Antiretroviral treatment (ART) does not reestablish these functionally impaired NK populations, and the expression of KLRG1 correlates with active HIV transcription. Targeting KLRG1 with specific antibodies significantly restores the capacity of NK cells to kill HIV-infected cells, reactivates latent HIV present in CD4+ T cells co-expressing KLRG1, and reduces the intact HIV genomes in samples from ART-treated individuals. Our data support the potential use of immunotherapy against the KLRG1 receptor to impact the viral reservoir during HIV persistence.
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Affiliation(s)
- Antonio Astorga-Gamaza
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - David Perea
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Nerea Sanchez-Gaona
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Marta Calvet-Mirabent
- Universidad Autónoma de Madrid, 28049 Madrid, Spain; Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
| | - Ana Gallego-Cortés
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Judith Grau-Expósito
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Ildefonso Sanchez-Cerrillo
- Universidad Autónoma de Madrid, 28049 Madrid, Spain; Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain
| | - Joan Rey
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Josep Castellví
- Department of Pathology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Adrian Curran
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Joaquin Burgos
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Jordi Navarro
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Paula Suanzes
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Vicenç Falcó
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Meritxell Genescà
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Enrique Martín-Gayo
- Universidad Autónoma de Madrid, 28049 Madrid, Spain; Immunology Unit from Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain; Infectious Diseases CIBER (CIBERINFECC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Buzon
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
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13
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Elanany MM, Mostafa D, Hamdy NM. Remodeled tumor immune microenvironment (TIME) parade via natural killer cells reprogramming in breast cancer. Life Sci 2023; 330:121997. [PMID: 37536617 DOI: 10.1016/j.lfs.2023.121997] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
Breast cancer (BC) is the main cause of cancer-related mortality among women globally. Despite substantial advances in the identification and management of primary tumors, traditional therapies including surgery, chemotherapy, and radiation cannot completely eliminate the danger of relapse and metastatic illness. Metastasis is controlled by microenvironmental and systemic mechanisms, including immunosurveillance. This led to the evolvement of immunotherapies that has gained much attention in the recent years for cancer treatment directed to the innate immune system. The long forgotten innate immune cells known as natural killer (NK) cells have emerged as novel targets for more effective therapeutics for BC. Normally, NK cells has the capacity to identify and eradicate tumor cells either directly or by releasing cytotoxic granules, chemokines and proinflammatory cytokines. Yet, NK cells are exposed to inhibitory signals by cancer cells, which causes them to become dysfunctional in the immunosuppressive tumor microenvironment (TME) in BC, supporting tumor escape and spread. Potential mechanisms of NK cell dysfunction in BC metastasis have been recently identified. Understanding these immunologic pathways driving BC metastasis will lead to improvements in the current immunotherapeutic strategies. In the current review, we highlight how BC evades immunosurveillance by rendering NK cells dysfunctional and we shed the light on novel NK cell- directed therapies.
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Affiliation(s)
- Mona M Elanany
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Dina Mostafa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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14
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Tamura T, Cheng C, Chen W, Merriam LT, Athar H, Kim YH, Manandhar R, Amir Sheikh MD, Pinilla-Vera M, Varon J, Hou PC, Lawler PR, Oldham WM, Seethala RR, Tesfaigzi Y, Weissman AJ, Baron RM, Ichinose F, Berg KM, Bohula EA, Morrow DA, Chen X, Kim EY. Single-cell transcriptomics reveal a hyperacute cytokine and immune checkpoint axis after cardiac arrest in patients with poor neurological outcome. MED 2023; 4:432-456.e6. [PMID: 37257452 PMCID: PMC10524451 DOI: 10.1016/j.medj.2023.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 03/06/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Most patients hospitalized after cardiac arrest (CA) die because of neurological injury. The systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. METHODS We determine the innate immune network induced by clinical CA at single-cell resolution. FINDINGS Immune cell states diverge as early as 6 h post-CA between patients with good or poor neurological outcomes 30 days after CA. Nectin-2+ monocyte and Tim-3+ natural killer (NK) cell subpopulations are associated with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies of peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. Interferon γ (IFNγ)/interleukin-10 (IL-10) induced Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. CONCLUSIONS The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints. FUNDING This work was supported by funding from the American Heart Association, Brigham and Women's Hospital Department of Medicine, the Evergreen Innovation Fund, and the National Institutes of Health.
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Affiliation(s)
- Tomoyoshi Tamura
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Changde Cheng
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Wenan Chen
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Louis T Merriam
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Humra Athar
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Yaunghyun H Kim
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Reshmi Manandhar
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Muhammad Dawood Amir Sheikh
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Mayra Pinilla-Vera
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Jack Varon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Peter C Hou
- Harvard Medical School, Boston, MA 02115, USA; Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Patrick R Lawler
- Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, ON M5G 2N2, Canada; McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - William M Oldham
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Raghu R Seethala
- Harvard Medical School, Boston, MA 02115, USA; Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Yohannes Tesfaigzi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Alexandra J Weissman
- Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Rebecca M Baron
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Fumito Ichinose
- Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Katherine M Berg
- Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Erin A Bohula
- Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - David A Morrow
- Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Xiang Chen
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Edy Y Kim
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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15
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Kachuri L, Hoffmann TJ, Jiang Y, Berndt SI, Shelley JP, Schaffer KR, Machiela MJ, Freedman ND, Huang WY, Li SA, Easterlin R, Goodman PJ, Till C, Thompson I, Lilja H, Van Den Eeden SK, Chanock SJ, Haiman CA, Conti DV, Klein RJ, Mosley JD, Graff RE, Witte JS. Genetically adjusted PSA levels for prostate cancer screening. Nat Med 2023; 29:1412-1423. [PMID: 37264206 PMCID: PMC10287565 DOI: 10.1038/s41591-023-02277-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 02/27/2023] [Indexed: 06/03/2023]
Abstract
Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.
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Affiliation(s)
- Linda Kachuri
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Thomas J Hoffmann
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Institute of Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Yu Jiang
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - John P Shelley
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Mitchell J Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Neal D Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Shengchao A Li
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Ryder Easterlin
- Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA, USA
| | | | - Cathee Till
- SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ian Thompson
- CHRISTUS Santa Rosa Medical Center Hospital, San Antonio, TX, USA
| | - Hans Lilja
- Departments of Laboratory Medicine, Surgery and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden
| | | | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Christopher A Haiman
- Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - David V Conti
- Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Robert J Klein
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonathan D Mosley
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rebecca E Graff
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
| | - John S Witte
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
- Departments of Biomedical Data Science and Genetics, Stanford University, Stanford, CA, USA.
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16
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Gurram RK, Wei D, Yu Q, Butcher MJ, Chen X, Cui K, Hu G, Zheng M, Zhu X, Oh J, Sun B, Urban JF, Zhao K, Leonard WJ, Zhu J. Crosstalk between ILC2s and Th2 cells varies among mouse models. Cell Rep 2023; 42:112073. [PMID: 36735533 PMCID: PMC10394112 DOI: 10.1016/j.celrep.2023.112073] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 01/03/2023] [Accepted: 01/23/2023] [Indexed: 02/04/2023] Open
Abstract
Type 2 T helper (Th2) cells and group 2 innate lymphoid cells (ILC2s) provide protection against helminth infection and are involved in allergic responses. However, their relative importance and crosstalk during type 2 immune responses are still controversial. By generating and utilizing mouse strains that are deficient in either ILC2s or Th2 cells, we report that interleukin (IL)-33-mediated ILC2 activation promotes the Th2 cell response to papain; however, the Th2 cell response to ovalbumin (OVA)/alum immunization is thymic stromal lymphopoietin (TSLP) dependent but independent of ILC2s. During helminth infection, ILC2s and Th2 cells collaborate at different phases of the immune responses. Th2 cells, mainly through IL-4 production, induce the expression of IL-25, IL-33, and TSLP, among which IL-25 and IL-33 redundantly promote ILC2 expansion. Thus, while Th2 cell differentiation can occur independently of ILC2s, activation of ILC2s may promote Th2 responses, and Th2 cells can expand ILC2s by inducing type 2 alarmins.
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Affiliation(s)
- Rama K Gurram
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
| | - Danping Wei
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Qiao Yu
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Gerontology and Respirology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Matthew J Butcher
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xi Chen
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kairong Cui
- Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Gangqing Hu
- Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Microbiology, Immunology, and Cell Biology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA
| | - Mingzhu Zheng
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xiaoliang Zhu
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jangsuk Oh
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
| | - Bing Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Joseph F Urban
- US Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD 20705, USA
| | - Keji Zhao
- Laboratory of Epigenome Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
| | - Jinfang Zhu
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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17
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Adeegbe D, Barbi J, Wing J. Editorial: Regulatory T lymphocytes in cancer immunity. Front Immunol 2022; 13:1065570. [PMID: 36353629 PMCID: PMC9639678 DOI: 10.3389/fimmu.2022.1065570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 10/14/2022] [Indexed: 10/13/2024] Open
Affiliation(s)
- Dennis Adeegbe
- Department of Immunology, H. Lee. Moffitt Cancer Center, Tampa, FL, United States
| | - Joseph Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - James Wing
- Human Immunology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
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18
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Monaco G, Khavaran A, Gasull AD, Cahueau J, Diebold M, Chhatbar C, Friedrich M, Heiland DH, Sankowski R. Transcriptome Analysis Identifies Accumulation of Natural Killer Cells with Enhanced Lymphotoxin-β Expression during Glioblastoma Progression. Cancers (Basel) 2022; 14:4915. [PMID: 36230839 PMCID: PMC9563981 DOI: 10.3390/cancers14194915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastomas are the most common primary brain tumors. Despite extensive clinical and molecular insights into these tumors, the prognosis remains dismal. While targeted immunotherapies have shown remarkable success across different non-brain tumor entities, they failed to show efficacy in glioblastomas. These failures prompted the field to reassess the idiosyncrasies of the glioblastoma microenvironment. Several high-dimensional single-cell RNA sequencing studies generated remarkable findings about glioblastoma-associated immune cells. To build on the collective strength of these studies, we integrated several murine and human datasets that profiled glioblastoma-associated immune cells at different time points. We integrated these datasets and utilized state-of-the-art algorithms to investigate them in a hypothesis-free, purely exploratory approach. We identified a robust accumulation of a natural killer cell subset that was characterized by a downregulation of activation-associated genes with a concomitant upregulation of apoptosis genes. In both species, we found a robust upregulation of the Lymphotoxin-β gene, a cytokine from the TNF superfamily and a key factor for the development of adaptive immunity. Further validation analyses uncovered a correlation of lymphotoxin signaling with mesenchymal-like glioblastoma regions in situ and in TCGA and CGGA glioblastoma cohorts. In summary, we identify lymphotoxin signaling as a potential therapeutic target in glioblastoma-associated natural killer cells.
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Affiliation(s)
- Gianni Monaco
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Single-Cell Omics Platform Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ashkan Khavaran
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Adrià Dalmau Gasull
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Jonathan Cahueau
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Martin Diebold
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Chintan Chhatbar
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Mirco Friedrich
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Dieter Henrik Heiland
- Department of Neurosurgery, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, 79106 Freiburg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center-University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, 79106 Freiburg, Germany
| | - Roman Sankowski
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Single-Cell Omics Platform Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
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19
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Loureiro Salgado C, Mendéz Corea AF, Covre LP, De Matos Guedes HL, Falqueto A, Gomes DCO. Ageing impairs protective immunity and promotes susceptibility to murine visceral leishmaniasis. Parasitology 2022; 149:1249-1256. [PMID: 35670372 PMCID: PMC11010576 DOI: 10.1017/s0031182022000828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/14/2022] [Accepted: 05/30/2022] [Indexed: 11/06/2022]
Abstract
It is well accepted that the impact of diseases is generally more detrimental in elderly individuals than in younger ones. Changes in the immune system due to ageing can directly affect the ability to respond effectively to infections and may contribute to the higher morbidities and mortalities in the elderly population. Leishmaniasis is a complex of clinically unique diseases caused by obligate intracellular protozoa belonging to genus Leishmania, wherein visceral leishmaniasis (VL) is the most severe form and is fatal if left untreated. In this study, aged mice (72 weeks old) presented increased susceptibility to L. infantum infection compared to younger mice (4–6-week-old), with notable parasitism in both the spleen and liver, as well as exhibiting hepatosplenomegaly. A pronounced inflammatory profile was observed in the aged-infected mice, with excessive production of TNF-α and nitrite, along with diminished IFN-γ production and reduced proliferative capacity of T cells (assessed by expression of the Ki67 marker). Additionally, both CD4+ and CD8+ T cells from the aged-infected mice presented increased expression of the inhibitory receptors PD-1 and KLRG1 that strongly correlated with the parasitism found in the liver and spleen of this group. Overall, the data reported in this study suggests for the first time that ageing may negatively impact the VL outcome and provides a perspective for new therapeutic strategies involving manipulation of immunosenescence features against Leishmania infection.
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Affiliation(s)
- Caio Loureiro Salgado
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitoria, Brazil
| | | | | | - Herbet Leonel De Matos Guedes
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
- Instituto de Microbiologia Professor Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Aloisio Falqueto
- Departamento de Medicina Social, Universidade Federal do Espírito Santo, Vitoria, Brazil
| | - Daniel Cláudio Oliviera Gomes
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitoria, Brazil
- Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Vitoria, Brazil
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20
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Qian H, Dong D, Fan P, Feng Y, Peng Y, Yao X, Wang R. Expression of KLRG1 on subpopulations of lymphocytes in the peripheral blood of patients with locally advanced nasopharyngeal carcinoma and prognostic analysis. PRECISION RADIATION ONCOLOGY 2022. [DOI: 10.1002/pro6.1165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Hengjun Qian
- Chinese Academy of Medical Sciences Key Laboratory of Cancer Immunotherapy and Radiotherapy The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- Xinjiang Key Laboratory of Oncology The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
| | - Danning Dong
- Chinese Academy of Medical Sciences Key Laboratory of Cancer Immunotherapy and Radiotherapy The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- Xinjiang Key Laboratory of Oncology The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
| | - Peiwen Fan
- Chinese Academy of Medical Sciences Key Laboratory of Cancer Immunotherapy and Radiotherapy The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- Xinjiang Key Laboratory of Oncology The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
| | - Yaning Feng
- Chinese Academy of Medical Sciences Key Laboratory of Cancer Immunotherapy and Radiotherapy The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- Xinjiang Key Laboratory of Oncology The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
| | - Yanchun Peng
- Chinese Academy of Medical Sciences Oxford Institute University of Oxford Oxford Oxfordshire UK
| | - Xuan Yao
- Chinese Academy of Medical Sciences Oxford Institute University of Oxford Oxford Oxfordshire UK
| | - Ruozheng Wang
- Chinese Academy of Medical Sciences Key Laboratory of Cancer Immunotherapy and Radiotherapy The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- Xinjiang Key Laboratory of Oncology The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi Xinjiang China
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia The Affiliated Tumor Hospital of Xinjiang Medical University Urumqi China
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21
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Borys SM, Bag AK, Brossay L, Adeegbe DO. The Yin and Yang of Targeting KLRG1 + Tregs and Effector Cells. Front Immunol 2022; 13:894508. [PMID: 35572605 PMCID: PMC9098823 DOI: 10.3389/fimmu.2022.894508] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
The literature surrounding KLRG1 has primarily focused on NK and CD8+ T cells. However, there is evidence that the most suppressive Tregs express KLRG1. Until now, the role of KLRG1 on Tregs has been mostly overlooked and remains to be elucidated. Here we review the current literature on KLRG1 with an emphasis on the KLRG1+ Treg subset role during cancer development and autoimmunity. KLRG1 has been recently proposed as a new checkpoint inhibitor target, but these studies focused on the effects of KLRG1 blockade on effector cells. We propose that when designing anti-tumor therapies targeting KLRG1, the effects on both effector cells and Tregs will have to be considered.
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Affiliation(s)
- Samantha M Borys
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, RI, United States
| | - Arup K Bag
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, RI, United States
| | - Dennis O Adeegbe
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
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22
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Zhou Y, Lan H, Shi H, Wu P, Zhou Y. Evaluating the diversity of circulating natural killer cells between active tuberculosis and latent tuberculosis infection. Tuberculosis (Edinb) 2022; 135:102221. [DOI: 10.1016/j.tube.2022.102221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/16/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022]
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23
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Poggi A, Zocchi MR. Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges. Mol Ther Oncolytics 2022; 24:26-42. [PMID: 34977340 PMCID: PMC8693432 DOI: 10.1016/j.omto.2021.11.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The discovery of immune checkpoints (ICs) and the development of specific blockers to relieve immune effector cells from this inhibiting mechanism has changed the view of anti-cancer therapy. In addition to cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed death 1 (PD1), classical ICs of T lymphocytes and recently described also on a fraction of natural killer (NK) cells, several NK cell receptors, including killer immunoglobulin-like inhibitory receptors (KIRs) and NGK2A, have been recognized as checkpoint members typical of the NK cell population. This offers the opportunity of a dual-checkpoint inhibition approach, targeting classical and non-classical ICs and leading to a synergistic therapeutic effect. In this review, we will overview and discuss this new perspective, focusing on the most relevant candidates for this role among the variety of potential NK ICs. Beside listing and defining classical ICs expressed also by NK cells, or non-classical ICs either on T or on NK cells, we will address their role in NK cell survival, chronic stimulation or functional exhaustion, and the potential relevance of this phenomenon on anti-tumor immune response. Furthermore, NK ICs will be proposed as possible new targets for the development of efficient combined immunotherapy, not forgetting the relevant concerns that may be raised on NK IC blockade. Finally, the impact of epigenetic drugs in such a complex therapeutic picture will be briefly addressed.
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Affiliation(s)
- Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, Building 90 Tower C, 4th Floor, 16132 Genoa, Italy
| | - Maria Raffaella Zocchi
- Division of Immunology, Transplants and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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24
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Buterez D, Bica I, Tariq I, Andrés-Terré H, Liò P. CellVGAE: an unsupervised scRNA-seq analysis workflow with graph attention networks. Bioinformatics 2021; 38:1277-1286. [PMID: 34864884 PMCID: PMC8825872 DOI: 10.1093/bioinformatics/btab804] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 10/27/2021] [Accepted: 11/24/2021] [Indexed: 01/05/2023] Open
Abstract
MOTIVATION Single-cell RNA sequencing allows high-resolution views of individual cells for libraries of up to millions of samples, thus motivating the use of deep learning for analysis. In this study, we introduce the use of graph neural networks for the unsupervised exploration of scRNA-seq data by developing a variational graph autoencoder architecture with graph attention layers that operates directly on the connectivity between cells, focusing on dimensionality reduction and clustering. With the help of several case studies, we show that our model, named CellVGAE, can be effectively used for exploratory analysis even on challenging datasets, by extracting meaningful features from the data and providing the means to visualize and interpret different aspects of the model. RESULTS We show that CellVGAE is more interpretable than existing scRNA-seq variational architectures by analysing the graph attention coefficients. By drawing parallels with other scRNA-seq studies on interpretability, we assess the validity of the relationships modelled by attention, and furthermore, we show that CellVGAE can intrinsically capture information such as pseudotime and NF-ĸB activation dynamics, the latter being a property that is not generally shared by existing neural alternatives. We then evaluate the dimensionality reduction and clustering performance on 9 difficult and well-annotated datasets by comparing with three leading neural and non-neural techniques, concluding that CellVGAE outperforms competing methods. Finally, we report a decrease in training times of up to × 20 on a dataset of 1.3 million cells compared to existing deep learning architectures. AVAILABILITYAND IMPLEMENTATION The CellVGAE code is available at https://github.com/davidbuterez/CellVGAE. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- David Buterez
- Department of Computer Science and Technology, University of Cambridge, Cambridge CB3 0FD, UK,To whom correspondence should be addressed.
| | - Ioana Bica
- Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK,The Alan Turing Institute, London NW1 2DB, UK
| | - Ifrah Tariq
- Computational and Systems Biology Program, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Helena Andrés-Terré
- Department of Computer Science and Technology, University of Cambridge, Cambridge CB3 0FD, UK
| | - Pietro Liò
- Department of Computer Science and Technology, University of Cambridge, Cambridge CB3 0FD, UK
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25
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Jacquelot N, Ghaedi M, Warner K, Chung DC, Crome SQ, Ohashi PS. Immune Checkpoints and Innate Lymphoid Cells-New Avenues for Cancer Immunotherapy. Cancers (Basel) 2021; 13:5967. [PMID: 34885076 PMCID: PMC8657134 DOI: 10.3390/cancers13235967] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/21/2022] Open
Abstract
Immune checkpoints (IC) are broadly characterized as inhibitory pathways that tightly regulate the activation of the immune system. These molecular "brakes" are centrally involved in the maintenance of immune self-tolerance and represent a key mechanism in avoiding autoimmunity and tissue destruction. Antibody-based therapies target these inhibitory molecules on T cells to improve their cytotoxic function, with unprecedented clinical efficacies for a number of malignancies. Many of these ICs are also expressed on innate lymphoid cells (ILC), drawing interest from the field to understand their function, impact for anti-tumor immunity and potential for immunotherapy. In this review, we highlight ILC specificities at different tissue sites and their migration potential upon inflammatory challenge. We further summarize the current understanding of IC molecules on ILC and discuss potential strategies for ILC modulation as part of a greater anti-cancer armamentarium.
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Affiliation(s)
- Nicolas Jacquelot
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (M.G.); (K.W.); (D.C.C.)
| | - Maryam Ghaedi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (M.G.); (K.W.); (D.C.C.)
| | - Kathrin Warner
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (M.G.); (K.W.); (D.C.C.)
| | - Douglas C. Chung
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (M.G.); (K.W.); (D.C.C.)
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada;
| | - Sarah Q. Crome
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (M.G.); (K.W.); (D.C.C.)
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada;
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26
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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27
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Host genetic control of natural killer cell diversity revealed in the Collaborative Cross. Proc Natl Acad Sci U S A 2021; 118:2018834118. [PMID: 33649222 DOI: 10.1073/pnas.2018834118] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Natural killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous antitumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive immune system variation that exists in the human population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC strains displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression, and functional capacities. We took advantage of the vast genetic diversity of the CC and identified nine genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94+ NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by host genetics.
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28
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Stutte S, Ruf J, Kugler I, Ishikawa-Ankerhold H, Parzefall A, Marconi P, Maeda T, Kaisho T, Krug A, Popper B, Lauterbach H, Colonna M, von Andrian U, Brocker T. Type I interferon mediated induction of somatostatin leads to suppression of ghrelin and appetite thereby promoting viral immunity in mice. Brain Behav Immun 2021; 95:429-443. [PMID: 33895286 DOI: 10.1016/j.bbi.2021.04.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/06/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
Loss of appetite (anorexia) is a typical behavioral response to infectious diseases that often reduces body weight. Also, anorexia can be observed in cancer and trauma patients, causing poor quality of life and reduced prospects of positive therapeutic outcomes. Although anorexia is an acute symptom, its initiation and endocrine regulation during antiviral immune responses are poorly understood. During viral infections, plasmacytoid dendritic cells (pDCs) produce abundant type I interferon (IFN-I) to initiate first-line defense mechanisms. Here, by targeted ablation of pDCs and various in vitro and in vivo mouse models of viral infection and inflammation, we identified that IFN-I is a significant driver of somatostatin (SST). Consequently, SST suppressed the hunger hormone ghrelin that led to severe metabolic changes, anorexia, and rapid body weight loss. Furthermore, during vaccination with Modified Vaccinia Ankara virus (MVA), the SST-mediated suppression of ghrelin was critical to viral immune response, as ghrelin restrained the production of early cytokines by natural killer (NK) cells and pDCs, and impaired the clonal expansion of CD8+ T cells. Thus, the hormonal modulation of ghrelin through SST and the cytokine IFN-I is fundamental for optimal antiviral immunity, which comes at the expense of calorie intake.
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Affiliation(s)
- Susanne Stutte
- Institute for Immunology, Faculty of Medicine, LMU Munich, Germany; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Janina Ruf
- Institute for Immunology, Faculty of Medicine, LMU Munich, Germany
| | - Ina Kugler
- Institute for Immunology, Faculty of Medicine, LMU Munich, Germany
| | | | - Andreas Parzefall
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Peggy Marconi
- Department of Chemical and Pharmaceutical Sciences (DipSCF), University of Ferrara, Italy
| | - Takahiro Maeda
- Departments of Island and Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1, Sakamoto, Nagasaki City, Japan
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Kimiidera 811-1, Wakayama 641-8509, Japan
| | - Anne Krug
- Institute for Immunology, Faculty of Medicine, LMU Munich, Germany
| | - Bastian Popper
- Biomedical Center (BMC), Core Facility Animal Models, Medical Faculty, LMU Munich, Germany
| | | | - Marco Colonna
- Washington University, School of Medicine, St. Louis, USA
| | - Ulrich von Andrian
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Thomas Brocker
- Institute for Immunology, Faculty of Medicine, LMU Munich, Germany.
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29
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Tata A, Dodard G, Fugère C, Leget C, Ors M, Rossi B, Vivier E, Brossay L. Combination blockade of KLRG1 and PD-1 promotes immune control of local and disseminated cancers. Oncoimmunology 2021; 10:1933808. [PMID: 34188973 PMCID: PMC8208121 DOI: 10.1080/2162402x.2021.1933808] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Checkpoint blockade therapy is effective against many cancers; however, new targets need to be identified to treat patients who do not respond to current treatment or demonstrate immune escape. Here, we showed that blocking the inhibitory receptor Killer cell lectin-like receptor G1 (KLRG1) enhances anti-tumor immunity mediated by NK cells and CD8+ T cells. We found that loss of KLRG1 signaling alone significantly decreased melanoma and breast cancer tumor growth in the lungs of mice. In addition, we demonstrated that KLRG1 blockade can synergize with PD-1 checkpoint therapy to increase the therapeutic efficacy compared to either treatment alone. This effect was even observed with tumors that do not respond to PD-1 checkpoint therapy. Double blockade therapy led to significantly decreased tumor size, increased frequency and activation of CD8+ T cells, and increased NK cell frequency and maturation in the tumor microenvironment. These findings demonstrate that KLRG1 is a novel checkpoint inhibitor target that affects NK and T cell anti-tumor immunity, both alone and in conjunction with established immunotherapies.
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Affiliation(s)
- Angela Tata
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, Rhode Island, USA
| | - Garvin Dodard
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, Rhode Island, USA
| | - Céline Fugère
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, Rhode Island, USA
| | | | - Mélody Ors
- Innate Pharma Research Labs., Marseille, France
| | | | - Eric Vivier
- Innate Pharma Research Labs., Marseille, France.,Centre d'Immunologie De Marseille-Luminy, Aix Marseille Université, Marseille, France.,Service d'Immunologie, Hôpital De La Timone, Assistance Publique-Hôpitaux De Marseille, Marseille, France
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, Rhode Island, USA.,Lead Contact
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Zhang Y, Li K, Li C, Liang W, Li K, Li J, Wei X, Yang J. An atypical KLRG1 in Nile tilapia involves in adaptive immunity as a potential marker for activated T lymphocytes. FISH & SHELLFISH IMMUNOLOGY 2021; 113:51-60. [PMID: 33798718 DOI: 10.1016/j.fsi.2021.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 06/12/2023]
Abstract
Killer cell lectin-like receptor G subfamily 1 (KLRG1) is a receptor generally expressed on effector CD8+ T cells or NK cells at terminal differentiation stage, and it will be highly induced for lymphocyte cytotoxicity upon pathogen infection or lymphocyte activation. However, little is known about the character or function of KLRG1 in lower vertebrates. In present study, we reappraised a molecule that previously defined as KLRG1 in the genomic sequence of Nile tilapia Oreochromis niloticus, and identified it as an atypical KLRG1-like molecule (defined as On-KLRG1-L), and illustrated its potential function serving as a marker representing effector T lymphocytes of fish species. On-KLRG1-L consists of two C-type lectin-like domains (CTLDs) without transmembrane region, and the tertiary structure of the CTLD is highly alike to that in mouse KLRG1. As a CTLD-containing protein, the recombinant On-KLRG1-L could bind PGN and several microbes in vitro. On-KLRG1-L was widely expressed in immune-associated tissues, with the highest expression level in the gill. Once Nile tilapia is infected by Aeromonas hydrophila, mRNA level of On-KLRG1-L in spleen lymphocytes were significantly up-regulated on 5 days after infection. Meanwhile, On-KLRG1-L protein was also induced on 5 or 8 days after A. hydrophila infection. Furthermore, we found both mRNA and protein levels of On-KLRG1-L were dramatically enhanced within several hours after spleen lymphocytes were activated by T cell-specific mitogen PHA in vitro. More importantly, the ratio of On-KLRG1-L+ T cells was also augmented after PHA stimulation. The observations suggested that the KLRG1-like molecule from Nile tilapia participated in lymphocyte activation and anti-bacterial adaptive immune response, and could serve as an activation marker of T lymphocytes. Our study thus provided new evidences to understand lymphocyte-mediated adaptive immunity of teleost.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Kang Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Cheng Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Wei Liang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Kunming Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jiaqi Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiumei Wei
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Jialong Yang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
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Ragab D, Samaha D, Mohamed N, Rafik M, Abdel Hady W. Chronic hepatitis C virus infection impairs natural killer cells-dendritic cells cross-talk: An in vitro culture study. Microbiol Immunol 2021; 65:76-84. [PMID: 33150993 DOI: 10.1111/1348-0421.12858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 12/24/2022]
Abstract
To examine the cross-talk between NK cells and DCs in hepatitis C virus (HCV) infection, we isolated monocytes and NK cells from 20 chronic HCV patients and 20 healthy controls. Monocytes were used to generate immature DCs which were pulsed with HCV peptides (core, NS3-NS4, and NS5). Four different cocultures were carried out: E1, both DCs and NK cells were from a chronic HCV patient; E2, NK cells from a healthy control cocultured with DCs from a chronic HCV patient; E3, NK cells from a chronic HCV patient cocultured with DCs from a healthy control; and E4, both DCs and NK cells were from a healthy control. Using flow cytometry, we assessed the effect of these different cocultures on levels of maturation markers on DCs and levels of activation/inhibition markers on NK cells. Results showed that peptide-pulsed HCV DCs showed a maturation defect in the form of decreased HLA-DR, decreased CD86, and increased CD83 expression especially when cocultured with HCV NK. This was mainly due to core peptide pulsing and to a lesser extent due to NS5 pulsing, whereas there was no effect with NS3-NS4 pulsing. Alternatively, HCV NK cells upregulated both activation and inhibition markers especially when cocultured with healthy DCs. Compared with E2, E1 resulted in higher apoptosis of both NK cells and DCs with the percentage of NK apoptosis higher than that of DCs. Taken together, the data indicate that HCV infection impairs NK-DC cross-talk which may be a leading cause in viral persistence and chronicity.
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Affiliation(s)
- Dina Ragab
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Dalia Samaha
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nesrine Mohamed
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mona Rafik
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Walid Abdel Hady
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Wang J, Matosevic S. Functional and metabolic targeting of natural killer cells to solid tumors. Cell Oncol (Dordr) 2020; 43:577-600. [PMID: 32488848 DOI: 10.1007/s13402-020-00523-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2020] [Indexed: 12/15/2022] Open
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Jevtovic A, Pantic J, Jovanovic I, Milovanovic M, Stanojevic I, Vojvodic D, Arsenijevic N, Lukic ML, Radosavljevic GD. Interleukin-33 pretreatment promotes metastatic growth of murine melanoma by reducing the cytotoxic capacity of CD8 + T cells and enhancing regulatory T cells. Cancer Immunol Immunother 2020; 69:1461-1475. [PMID: 32285171 DOI: 10.1007/s00262-020-02522-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/15/2020] [Indexed: 01/08/2023]
Abstract
Interleukin-33 (IL-33) regulates innate and acquired immune response to pathogens, self-antigens and tumors. IL-33 effects on tumors depend on the dose and mode of administration along with the type of malignancy. We studied the effects of IL-33 on the development of primary and metastatic melanoma induced by B16-F1 cell line in C57BL/6 mice. Intraperitoneally applied IL-33 restricts primary tumor growth. When administered intranasally 3 days prior to the intravenous injection of the tumor cells, IL-33 promoted growth of B16-F1 melanoma metastases, while B16-F10 gave massive metastases independently of IL-33. To mimic natural dissemination, we next used a limited number (5 × 104) of B16-F1 cells intravenously followed by application of IL-33 intraperitoneally. IL-33 increased the size of metastases (10.96 ± 3.96 mm2) when compared to the control group (0.86 ± 0.39 mm2), without changing incidence and number of metastases. IL-33 increased expression of ST2 on both tumor and immune cells in metastases. Also, IL-33 enhanced eosinophils and anti-tumor NK cells in the lung. The striking finding was reduced cytotoxicity of CD8+ T cells derived from metastatic lung of IL-33 injected mice. IL-33 reduced the percentage of TNF-α+ and IFN-γ+ CD8+ T cells while increasing the frequency of CD8+ T cells that express inhibitory molecules (PD-1, KLRG-1 and CTLA-4). There was a significant accumulation of CD11b+Gr-1+ myeloid suppressor cells and FoxP3+, IL-10+ and CTLA-4+ regulatory T cells in the metastatic lung of IL-33 injected mice. The relevance of IL-33 for melanoma metastases was also documented in a significantly increased level of serum IL-33 in stage III melanoma patients.
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Affiliation(s)
- Andra Jevtovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.,Department of Otorhinolaryngology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Pantic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Ivan Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Ivan Stanojevic
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Danilo Vojvodic
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Miodrag L Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.
| | - Gordana D Radosavljevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.
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Wu N, Li J, Chen X, Xiang Y, Wu L, Li C, Zhang H, Tong S, Zhong L, Li Y. Identification of Long Non-Coding RNA and Circular RNA Expression Profiles in Atrial Fibrillation. Heart Lung Circ 2019; 29:e157-e167. [PMID: 31843366 DOI: 10.1016/j.hlc.2019.10.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/24/2019] [Accepted: 10/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Long non-coding RNA (lncRNA) and circular RNA (circRNA) have both been found to play important roles in cardiovascular diseases, including myocardial infarction, heart failure, and atherosclerosis. However, the role of lncRNA and circRNA in atrial fibrillation (AF) has rarely been investigated. This study aimed to identify lncRNA and circRNA expression profiles in AF patients. METHODS Atrial tissues from seven patients with AF and seven matched controls were collected. The lncRNA and circRNA expression profiles of atrial tissues were identified using Hiseq/Proton RNA sequencing. Validation was performed by reverse transcription quantitative real-time PCR (qRT-PCR) on 35 pairs of AF patients and controls. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A competing endogenous RNA (ceRNA) network was constructed. RESULTS A total of 557 lncRNAs and 280 circRNAs were significantly differentially expressed with fold change >1.5 (p<0.05). An lncRNA Voltage Dependent Anion Channel 2 Pseudogene 2 (VDAC2P2) and two circRNAs chr13_41887361_41865736_-21625 and chr13_100368574_100301460_-67114 were validated, using qRT-PCR, to have significantly different expression levels. GO and KEGG pathway analysis showed that some pathways such as ribosome and chromatin modification, Rap1 signalling and cardiac muscle contraction were involved in the pathogenesis of AF. Competing endogenous RNAs were predicted based on constructional network analysis. The LncRNA-miRNA-mRNA and circRNA-miRNA-mRNA networks were constructed by co-expressing lncRNA/circRNA and mRNAs, which were competitively combined with miRNAs. CONCLUSION This study characterised lncRNA and circRNA expression and their interaction with mRNA and miRNA in AF.
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Affiliation(s)
- Na Wu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Jun Li
- Thoracic and Cardiac Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Xinghua Chen
- Department of Cardiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Ying Xiang
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Long Wu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Chengying Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Huan Zhang
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China
| | - Shifei Tong
- Cardiovascular Disease Center, Third Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Li Zhong
- Cardiovascular Disease Center, Third Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Yafei Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University (Third Military Medical University), Chongqing, People's Republic of China.
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Mele D, Pasi A, Cacciatore R, Mantovani S, Oliviero B, Mondelli MU, Varchetta S. Decreased interferon-γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection. Liver Int 2019; 39:1237-1245. [PMID: 31177636 DOI: 10.1111/liv.14172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 06/03/2019] [Accepted: 06/04/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIMS Different population genetics studies showed that interactions between killer-cell immunoglobulin-like receptors (KIR) and HLA play a role in viral disease outcome, but functional correlates are missing. Building upon our previous work pointing to a regulatory role for KIR3DL1/DS1 in hepatitis C virus (HCV) infection, we analysed whether its expression may affect natural killer (NK) cell function in the presence or absence of its principal ligand HLA-Bw4 in KIR haplotype A and B carriers, which are characterized by a different representation of activating and inhibitory KIRs. METHODS We performed KIR and HLA class I genotypic analysis in 54 healthy donors (HD) and 50 HCV+ subjects and examined NK cell cytokine secretion and degranulation in the context of KIR3DL1-HLA-Bw4 match stratified by KIR haplotype. RESULTS KIR3DL1-HLA-Bw4 match induced functional NK cell modulation, reflected by reduced interferon (IFN)γ production in haplotype B HCV+ patients compared to HD. This functional impairment could be ascribed to the KIR3DS1 negative HCV-infected patient population, whose NK cells also showed a significantly decreased proportion of KIR3DL1. Haplotype A HCV-infected patients showed increased NK cell degranulation compared with HD in the absence of KIR-HLA-Bw4 match and this activity was associated with increased phosphorylation of signal transducer and activator of transcription (STAT) 1. CONCLUSIONS Our data show that NK cells from HCV+ patients have an unbalanced ability to produce IFNγ and to kill target cells in haplotype A and B carriers, suggesting the existence of complex functional differences governed by KIR-HLA interaction, particularly on KIR3DL1 expressing NK cells.
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Affiliation(s)
- Dalila Mele
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Annamaria Pasi
- Laboratory of Immunogenetics, Department of Transfusion Medicine and Immuno-Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Rosalia Cacciatore
- Laboratory of Immunogenetics, Department of Transfusion Medicine and Immuno-Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefania Mantovani
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Barbara Oliviero
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mario U Mondelli
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Stefania Varchetta
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Hu Z, Zhao HM, Li CL, Liu XH, Barkan D, Lowrie DB, Lu SH, Fan XY. The Role of KLRG1 in Human CD4+ T-Cell Immunity Against Tuberculosis. J Infect Dis 2019; 217:1491-1503. [PMID: 29373700 DOI: 10.1093/infdis/jiy046] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/22/2017] [Indexed: 01/29/2023] Open
Abstract
Background KLRG1 is a marker of terminally differentiated CD8+ T cells in viral infection, but its role in human Mycobacterium tuberculosis infection remains elusive. Methods A set of cohorts of patients with tuberculosis was designed, and the expression profiles and functions of KLRG1+CD4+ T cells were determined with and without antibody blocking. Results KLRG1 expression on CD4+ T cells was significantly increased in patients with active tuberculosis, compared with healthy controls and patients without tuberculosis. Upon M. tuberculosis-specific stimulation, the ability to secrete interferon γ, interleukin 2, and tumor necrosis factor α was significantly greater in KLRG1-expressing CD4+ T cells than in their KLRG-negative counterparts and was accompanied by a decreased proportion of regulatory T cells and increased Akt signaling. However, KLRG1-expressing CD4+ T cells had a shorter life-span, which was associated with a higher apoptosis rate but a similar proliferative response. Blockade of KLRG1 signaling significantly enhanced interferon γ and interleukin 2 secretion without affecting either cell apoptosis or multiplication. Addition of a specific Akt inhibitor prevented this increased cytokine response, implicating the Akt signaling pathway. Conclusions Our study delineated the profile of KLRG1+CD4+ T cells in patients with tuberculosis and suggests that M. tuberculosis infection drives CD4+ T cells to acquire increased effector function in a terminally differentiated state, which is restrained by KLRG1 via KLRG1/Akt signaling pathway.
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Affiliation(s)
- Zhidong Hu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University.,TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai
| | - Hui-Min Zhao
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University
| | - Chun-Ling Li
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Xu-Hui Liu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University.,TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai
| | - Daniel Barkan
- Koret School of Veterinary Medicine, Hebrew University, Rehovot, Israel
| | - Douglas B Lowrie
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University.,TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai
| | - Shui-Hua Lu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University.,TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai.,School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Xiao-Yong Fan
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University.,TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai.,School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
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Alvarez M, Simonetta F, Baker J, Pierini A, Wenokur AS, Morrison AR, Murphy WJ, Negrin RS. Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. JCI Insight 2019; 5:127729. [PMID: 31211693 DOI: 10.1172/jci.insight.127729] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE characterized by up-regulation of the terminal differentiation marker KLRG1 and by down-regulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimized NCE compared to control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulations on NK cells has been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation there is an increase of MULT1, and NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, by sustaining NKG2D expression and by preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased anti-tumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell-based immunotherapy.
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Affiliation(s)
- Maite Alvarez
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - Federico Simonetta
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - Jeanette Baker
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - Antonio Pierini
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - Arielle S Wenokur
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - Alyssa R Morrison
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
| | - William J Murphy
- Department of Dermatology and Internal Medicine, University of California, Davis, Sacramento, California, USA
| | - Robert S Negrin
- Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California, USA
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Greenberg SA, Kong SW, Thompson E, Gulla SV. Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models. Oncotarget 2019; 10:1399-1406. [PMID: 30858925 PMCID: PMC6402715 DOI: 10.18632/oncotarget.26659] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 01/21/2019] [Indexed: 01/22/2023] Open
Abstract
Background KLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells. Targeting of KLRG1 neutralization in murine cancer models has not previously been reported. Methods We studied KLRG1 expression in human blood and tumor samples from available genomic datasets. Anti-KLRG1 neutralizing antibody was studied in the murine 4T1 breast cancer as monotherapy, and in the MC38 colon cancer and B16F10 melanoma models as combination therapy with anti-PD-1 antibody. Results In human blood and tumor samples, KLRG1 expression is aligned with cytotoxic T and NK cell differentiation, and upregulated in human tumor samples after a variety of therapies, potentially contributing to adaptive resistance. In in vivo murine models, anti-KLRG1 antibody monotherapy in the 4T1 breast cancer model reduced lung metastases (decreased lung weights p=0.04; decreased nodule count p=0.002), while anti-KLRG1 + anti-PD-1 combination therapy in the MC38 colon cancer and B16F10 melanoma models produced synergistic benefit greater than anti-PD-1 alone for tumor volume (MC38 p=0.01; B16F10 p=0.007) and survival (MC38 p=0.02; B16F10 p=0.002). Conclusions These studies provide the first evidence that inhibition of the KLRG1 pathway enhances immune control of cancer in murine models, and provide target validation for KLRG1 targeting of human cancer. The mechanism of efficacy of KLRG1 blockade in murine models remains to be determined.
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Affiliation(s)
- Steven A Greenberg
- Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
| | - Sek Won Kong
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
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Covre LP, Martins RF, Devine OP, Chambers ES, Vukmanovic-Stejic M, Silva JA, Dietze R, Rodrigues RR, de Matos Guedes HL, Falqueto A, Akbar AN, Gomes DCO. Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis. Front Immunol 2019; 9:3001. [PMID: 30662437 PMCID: PMC6328442 DOI: 10.3389/fimmu.2018.03001] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 12/04/2018] [Indexed: 11/13/2022] Open
Abstract
Leishmania (Viannia) braziliensis induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and γH2AX that have short telomeres and low hTERT expression during cutaneous L. braziliensis infection. This expanded population of T cells was found within the CD45RA+CD27- (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the Leishmania-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease.
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Affiliation(s)
- Luciana P Covre
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Régia F Martins
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Oliver P Devine
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Emma S Chambers
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Juliana A Silva
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Reynaldo Dietze
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil.,Saúde Global e Medicina Tropical, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Rodrigo R Rodrigues
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Herbert L de Matos Guedes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Aloísio Falqueto
- Departamento de Medicina Social, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Arne N Akbar
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Daniel C O Gomes
- Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil.,Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Brazil
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40
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Fantini M, David JM, Wong HC, Annunziata CM, Arlen PM, Tsang KY. An IL-15 Superagonist, ALT-803, Enhances Antibody-Dependent Cell-Mediated Cytotoxicity Elicited by the Monoclonal Antibody NEO-201 Against Human Carcinoma Cells. Cancer Biother Radiopharm 2019; 34:147-159. [PMID: 30601063 PMCID: PMC6482908 DOI: 10.1089/cbr.2018.2628] [Citation(s) in RCA: 18] [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] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND A major mechanism of action for therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC). ALT-803 is an interleukin-15 superagonist complex that enhances ADCC against human carcinoma cells in vitro and exerts an antitumor activity in murine, rat, and human carcinomas in vivo. The authors investigated the ability of ALT-803 to modulate ADCC mediated by the humanized IgG1 monoclonal antibody (mAb) NEO-201 against human carcinoma cells. MATERIALS AND METHODS ALT-803 modulating activity on ADCC mediated by NEO-201 was evaluated on several NEO-201 ligand-expressing human carcinoma cells. Purified human natural killer (NK) cells from multiple healthy donors were treated with ALT-803 before their use as effectors in ADCC assay. Modulation of NK cell phenotype and cytotoxic function by exposure to ALT-803 was evaluated by flow cytometry and gene expression analysis. RESULTS ALT-803 significantly enhanced ADCC mediated by NEO-201. ALT-803 also upregulated NK activating receptors, antiapoptotic factors, and factors involved in the NK cytotoxicity, as well as downregulated gene expression of NK inhibiting receptors. CONCLUSIONS These findings indicate that ALT-803 can enhance ADCC activity mediated by NEO-201, by modulating NK activation and cytotoxicity, suggesting a possible clinical use of ALT-803 in combination with NEO-201 for the treatment of human carcinomas.
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Affiliation(s)
| | | | | | - Christina M. Annunziata
- Women's Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | | | - Kwong Y. Tsang
- Precision Biologics, Inc., Rockville, Maryland
- Address correspondence to: Kwong Y. Tsang; Precision Biologics, Inc.; 9600 Medical Center Drive, Suite 300, Rockville, MD 20850
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41
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Zheng M, Sun H, Tian Z. Natural killer cells in liver diseases. Front Med 2018; 12:269-279. [PMID: 29675689 DOI: 10.1007/s11684-018-0621-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022]
Abstract
The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct "killer" functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.
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Affiliation(s)
- Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Haoyu Sun
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China
| | - Zhigang Tian
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
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42
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PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 2018; 7:72961-72977. [PMID: 27662664 PMCID: PMC5341956 DOI: 10.18632/oncotarget.12150] [Citation(s) in RCA: 244] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 09/13/2016] [Indexed: 12/14/2022] Open
Abstract
Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.
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43
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Radosavljevic GD, Pantic J, Jovanovic I, Lukic ML, Arsenijevic N. The Two Faces of Galectin-3: Roles in Various Pathological Conditions. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2016. [DOI: 10.1515/sjecr-2016-0011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Galectin-3, a unique chimaera-type member of the lectin family, displays a wide range of activities. This versatile molecule is involved in fundamental biological processes, including cell proliferation, cell-cell adhesion, apoptosis and immune responses.
This review is aimed at providing a general overview of the biological actions and diverse effects of Galectin-3 in many pathological conditions, with a specific focus on autoimmunity, inflammation and tumour progression. We report herein that Galectin-3 exerts deleterious functions determined by promotion of tumour progression and liver inflammation or aggravation of T cell-mediated autoimmune diseases. On the other hand, Galectin-3 exhibits a protective role in metabolic abnormalities and primary biliary cirrhosis.
The paradoxical “yin and yang” functions of Galectin-3 depend not only on its tissue and cellular localization but also on its availability, glycosylation status and the expression level of its ligands.
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Affiliation(s)
- Gordana D. Radosavljevic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Jelena Pantic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Ivan Jovanovic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Miodrag L. Lukic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Nebojsa Arsenijevic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
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44
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Müller-Durovic B, Lanna A, Covre LP, Mills RS, Henson SM, Akbar AN. Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5'-Monophosphate-Activated Protein Kinase. THE JOURNAL OF IMMUNOLOGY 2016; 197:2891-2899. [PMID: 27566818 DOI: 10.4049/jimmunol.1600590] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 08/01/2016] [Indexed: 01/10/2023]
Abstract
NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity was shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of infectious diseases and malignancy rises dramatically, suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1 (KLRG1) in individuals >70 y. The role of KLRG1 in ageing is not known, and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. We report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory dephosphorylation by protein phosphatase-2C rather than inducing de novo kinase activation. Finally, inhibition of KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reductions in NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression. This novel signaling pathway links metabolic sensing, effector function, and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing.
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Affiliation(s)
| | - Alessio Lanna
- Division of Infection and Immunity, University College London, London, UK.,Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Luciana Polaco Covre
- Division of Infection and Immunity, University College London, London, UK.,Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Rachel S Mills
- Division of Infection and Immunity, University College London, London, UK
| | - Sian M Henson
- William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Arne N Akbar
- Division of Infection and Immunity, University College London, London, UK
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45
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Claus M, Dychus N, Ebel M, Damaschke J, Maydych V, Wolf OT, Kleinsorge T, Watzl C. Measuring the immune system: a comprehensive approach for the analysis of immune functions in humans. Arch Toxicol 2016; 90:2481-95. [DOI: 10.1007/s00204-016-1809-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 08/04/2016] [Indexed: 12/14/2022]
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46
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Yoon JC, Yang CM, Song Y, Lee JM. Natural killer cells in hepatitis C: Current progress. World J Gastroenterol 2016; 22:1449-1460. [PMID: 26819513 PMCID: PMC4721979 DOI: 10.3748/wjg.v22.i4.1449] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/30/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Patients infected with the hepatitis C virus (HCV) are characterized by a high incidence of chronic infection, which results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The functional impairment of HCV-specific T cells is associated with the evolution of an acute infection to chronic hepatitis. While T cells are the important effector cells in adaptive immunity, natural killer (NK) cells are the critical effector cells in innate immunity to virus infections. The findings of recent studies on NK cells in hepatitis C suggest that NK cell responses are indeed important in each phase of HCV infection. In the early phase, NK cells are involved in protective immunity to HCV. The immune evasion strategies used by HCV may target NK cells and might contribute to the progression to chronic hepatitis C. NK cells may control HCV replication and modulate hepatic fibrosis in the chronic phase. Further investigations are, however, needed, because a considerable number of studies observed functional impairment of NK cells in chronic HCV infection. Interestingly, the enhanced NK cell responses during interferon-α-based therapy of chronic hepatitis C indicate successful treatment. In spite of the advances in research on NK cells in hepatitis C, establishment of more physiological HCV infection model systems is needed to settle unsolved controversies over the role and functional status of NK cells in HCV infection.
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47
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Quarleri JF, Oubiña JR. Hepatitis C virus strategies to evade the specific-T cell response: a possible mission favoring its persistence. Ann Hepatol 2016; 15:17-26. [PMID: 26626636 DOI: 10.5604/16652681.1184193] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a small, enveloped RNA virus. The number of HCV-infected individuals worldwide is estimated to be approximately 200 million. The vast majority of HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. The interaction between HCV and the host have a pivotal role in viral fitness, persistence, pathogenicity, and disease progression. The control of HCV infection requires both effective innate and adaptive immune responses. The HCV clearance during acute infection is associated with an early induction of the innate and a delayed initiation of the adaptive immune responses. However, in the vast majority of acute HCV infections, these responses are overcome and the virus persistence almost inexorably occurs. Recently, several host- and virus-related mechanisms responsible for the failure of both the innate and the adaptive immune responses have been recognized. Among the latter, the wide range of escape mutations to evade the specific-T-and B-cell responses as well as the T cell anergy and the CD8+ T cell exhaustion together with the interference with its function after prolonged virus exposure hold a pivotal role. Other HCV strategies include the modification or manipulation of molecules playing key roles in the induction of the interferon response and its induced effector proteins. In this review, we attempt to gain insights on the main T cell immune evasion strategies used by the virus in order to favor its persistence.
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Affiliation(s)
- Jorge Fabián Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires-CONICET, Argentina
| | - José Raúl Oubiña
- Instituto de Microbiología y Parasitología Médica (IMPAM), Universidad de Buenos Aires-CONICET, Argentina
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48
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Martínez-Esparza M, Tristán-Manzano M, Ruiz-Alcaraz AJ, García-Peñarrubia P. Inflammatory status in human hepatic cirrhosis. World J Gastroenterol 2015; 21:11522-11541. [PMID: 26556984 PMCID: PMC4631958 DOI: 10.3748/wjg.v21.i41.11522] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
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49
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Cheng YQ, Ren JP, Zhao J, Wang JM, Zhou Y, Li GY, Moorman JP, Yao ZQ. MicroRNA-155 regulates interferon-γ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection. Immunology 2015; 145:485-97. [PMID: 25772938 DOI: 10.1111/imm.12463] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 02/20/2015] [Accepted: 03/11/2015] [Indexed: 12/17/2022] Open
Abstract
Host immune responses must be tightly regulated by an intricate balance between positive and negative signals while fighting pathogens; persistent pathogens may usurp these regulatory mechanisms to dampen host immunity to facilitate survival in vivo. Here we report that Tim-3, a negative signalling molecule expressed on monocytes and T cells, is up-regulated on natural killer (NK) cells in individuals chronically infected with hepatitis C virus (HCV). Additionally, the transcription factor T-bet was also found to be up-regulated and associated with Tim-3 expression in NK cells during chronic HCV infection. MicroRNA-155 (miR-155), an miRNA that inhibits signalling proteins involved in immune responses, was down-regulated in NK cells by HCV infection. This Tim-3/T-bet over-expression and miR-155 inhibition were recapitulated in vitro by incubating primary NK cells or NK92 cell line with Huh-7 hepatocytes expressing HCV. Reconstitution of miR-155 in NK cells from HCV-infected patients led to a decrease in T-bet/Tim-3 expression and an increase in interferon-γ production. Blocking Tim-3 signalling also enhanced interferon-γ production in NK cells by improving signal transducer and activator of transcription-5 phosphorylation. These data indicate that HCV-induced, miR-155-regulated Tim-3 expression regulates NK cell function, suggesting a novel mechanism for balancing immune clearance and immune injury during chronic viral infection.
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Affiliation(s)
- Yong Q Cheng
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,International Centre for Diagnosis and Treatment of Liver Diseases, Beijing, China
| | - Jun P Ren
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Juan Zhao
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Jia M Wang
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Department of Biochemistry and Molecular Biology, Soochow University School of Medicine, Suzhou, China
| | - Yun Zhou
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Centre of Diagnosis and Treatment for Infectious Diseases of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xian, China
| | - Guang Y Li
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Jonathan P Moorman
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,HCV/HIV Program, James H. Quillen VA Medical Center, Johnson City, TN, USA
| | - Zhi Q Yao
- Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,HCV/HIV Program, James H. Quillen VA Medical Center, Johnson City, TN, USA
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50
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Zhou Y, Zhang Y, Moorman JP, Yao ZQ, Jia ZS. Viral (hepatitis C virus, hepatitis B virus, HIV) persistence and immune homeostasis. Immunology 2014; 143:319-30. [PMID: 24965611 DOI: 10.1111/imm.12349] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/18/2014] [Accepted: 06/19/2014] [Indexed: 12/14/2022] Open
Abstract
Immune homeostasis is a host characteristic that maintains biological balance within a host. Humans have evolved many host defence mechanisms that ensure the survival of individuals upon encountering a pathogenic infection, with recovery or persistence from a viral infection being determined by both viral factors and host immunity. Chronic viral infections, such as hepatitis B virus, hepatitis C virus and HIV, often result in chronic fluctuating viraemia in the face of host cellular and humoral immune responses, which are dysregulated by multi-faceted mechanisms that are incompletely understood. This review attempts to illuminate the mechanisms involved in this process, focusing on immune homeostasis in the setting of persistent viral infection from the aspects of host defence mechanism, including interferon-stimulated genes, apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3), autophagy and interactions of various immune cells, cytokines and regulatory molecules.
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Affiliation(s)
- Yun Zhou
- Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China; Center for Inflammation, Infectious Diseases, and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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