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exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

Cellular & Molecular Immunology 2020年第1期17卷 27-35页

作者： Yangjing Zhao Qixiang Shao Guangyong Peng Division of Infectious Diseases Allergy&Immunology and Department of Internal MedicineSaint Louis University School of MedicineSaint LouisMO 63104USA Department of Immunology Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu ProvinceSchool of MedicineJiangsu UniversityZhenjiang 212013P.R.China Department of Molecular Microbiology&Immunology Saint Louis University School of MedicineSt.LouisMO 63104USA

The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors.T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients,hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor *** exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity,they are distinctly different in terms of generation,development,and metabolic and molecular regulation during tumor ***,we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and *** addition,we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor *** these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

关键词： T-cell dysfunction exhaustion Senescence Tumor microenvironment Inhibitory receptor Metabolism Checkpoint blockade

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A preliminary analysis of fishery resource exhaustion in the context of biodiversity decline

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Science China Earth Sciences 2016年第11期59卷 223-235页

作者： ZHAO ShuJiang Lü BaoQiang LI RuWei ZHU AiYi WU ChangWen School of Marine Science and Technology Zhejiang Ocean University Zhoushan 316022 China Marine Environmental Monitoring Central Station of Wenzhou State Oceanic Administration People's Republic of China Wenzhou 325013 China

Marine biodiversity in almost all oceans is being threatened at the genetic, species, and ecosystem levels. The marine ecosystem is being degraded and the extinction rate of marine organisms has accelerated. In this paper, the potential causes of fishery resource exhaustion in the East China Sea are analyzed, including the change in the stoichiometric composition of seawater with regard to the concentrations of N and P, toxic effects of marine pollution, marine habitat destruction, increased seawater temperatures caused by climate warming, ocean acidification, pressure from overfishing, and the spread of marine pathogenic bacteria. It is believed that the factors mentioned above have significant impact on the exhaustion of fishery resources in the East China Sea. However, considering the cumulative, synergistic, and superimposed effects as well as the amplification effects resulting from their interactions, the actual risk of ecological extinction of marine organisms might be even more severe than that previously estimated. Hence, ecosystem management and research focused on a single risk factor or influencing factor is not enough to prevent marine ecosystem degradation and fishery resource exhaustion. A comprehensive, systematic, effective, and ecosystem-based management policy is imperative for healthy and sustainable fishery development in the East China Sea.

关键词： Fishery resources exhaustion Extinction Influencing factor Cumulative effect Superimposed effect Amplifi-cation effect

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exhaustion and Emotional Demands in China： A Large-Scale Investigation across Occupations

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Frontiers of Business Research in China 2017年第1期11卷 45-68页

作者： Kelly Z. Peng Department of Business Administration Hong Kong Shue Yan University Hong Kong China

As the Chinese economy moves toward a market-based model, employees are likely to face more emotional demands and exhaustion at work. However, there are some unique aspects to the emotional demands of work in the Chinese cultural context. We investigate emotional demands and exhaustion in China with a large-scale sample across the six major occupations identified by the Holland classification system. Results show that incumbents of social and enterprising jobs face higher emotional demands. Unexpectedly, exhaustion differs significantly between conventional and other types of jobs. Building on the Job Demand-Resources （JD-R） model, job crafting and the cultural context, we propose that the nonlinear relationship of emotional demands and exhaustion exists only when emotional intelligence is low. Our study may inform practitioners and policy makers in Chinese enterprises about emotional demands and exhaustion for various occupations and the importance of selection and training programs in emotional intelligence.

关键词： exhaustion burnout emotional demands emotional intelligence JD-R model

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Transcriptional suppression of CD8^(+)T cell exhaustion for improving T cell immunotherapy

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Cancer Communications 2021年第11期41卷 1228-1231页

作者： Xue Yang Bingjing Wang Xuetao Cao Department of Immunology Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005P.R.China College of Life Sciences Nankai UniversityTianjin 300071P.R.China

As the major effector of cellular adaptive immune response,CD8^(+) T cells play crucial roles in the host’s defense against tumor and *** recent studies revealed that basic leucine zipper ATF-like transcriptional factor(BATF)not only blocks the exhaustion of CD8^(+) engineered chimeric antigen receptor(CAR)-T cells,but also regulates the differentiation of stem-like CD8^(+) T precursor cells into effector cells during chronic infection[1,2].These results emphasized the important roles of transcriptional regulation in promoting T cell effector functions and preventing T cell exhaustion as well,suggesting the potential application of motivating transcriptional regulators such as BATF to improve the efficacy of adaptive T cell immunotherapy of cancer and chronic infection.

关键词： immunotherapy exhaustion infection

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A Health Impairment Process of Sickness Presenteeism in Norwegian Physicians: The Mediating Role of exhaustion

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Health 2016年第9期8卷 846-856页

作者： Sylvi Thun Lise T. Løvseth Department of Psychology Norwegian University of Science and Technology (NTNU) Trondheim Norway Department of Research and Development Division of Psychiatry St Olav’s Hospital Trondheim Norway

Although work factors have been associated with both presenteeism and exhaustion among hospital physicians, we lack knowledge on the dynamic relationship between demands in the work context and presenteeism and how this can be mediated by symptoms of exhaustion when controlling for job resources. The objective of this study is to examine a health impairment process of presenteeism among university hospital physicians. A cross-sectional survey of 545 university hospital physicians in Norway was conducted. Variables included in the model were presenteeism, exhaustion, work-family conflict, role conflict, social support and control over work pace. Findings from structural equation modeling indicated that exhaustion mediates the relationship between job demands and presenteeism. Job resources had no direct effect on presenteeism in the hypothesized model. The variables in the study explained 17% of the variance in presenteeism. The study is one of the first to demonstrate that the relationship between job demands and presenteeism is mediated by exhaustion when controlling for job resources. The results highlight the importance of considering the link between health symptoms and job demands to reduce the negative effects of presenteeism.

关键词： Sickness Presenteeism exhaustion Job Demands Job Resources JD-R Theory

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Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection

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World Journal of Vaccines 2019年第1期9卷 1-21页

作者： Aizhang Xu Xueying Zhang Rajni Chibbar Andrew Freywald Suresh Tikoo Changyu Zheng Jim Xiang Cancer Research Saskatchewan Cancer Agency Saskatoon Canada Department of Oncology College of Medicine University of Saskatchewan Saskatoon Canada Department of Pathology College of Medicine University of Saskatchewan Saskatoon Canada School of Public Health University of Saskatchewan Saskatoon Canada Molecular Physiology and Therapeutic Branch National Institute of Dental and Craniofacial Research National Institute of Health Bethesda USA

CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic va

关键词： IL-21 Chronic Infection CTL exhaustion Exosome T Cell Vaccine

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The exhaustion Doctrine and Related Antitrust Issues

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今日财富（中国知识产权） 2010年第3期 70-74页

作者： William Rowland Buchanan Ingersoll & Rooney PC

A ccording to the exhaustion Doctrine,when a patented item is lawfully made and sold, the patent owner exhausts its rights in the ***,exhaustion is

关键词： exhaustion owner patent authorized license triggered doctrine manufacture contract filed

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OBSERVATION ON THERAPEUTIC EFFECTS OF FENGJIU THERAPY IN 300 CASES OF exhaustion SYNDROME

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World Journal of Acupuncture-Moxibustion 1997年第3期7卷 58-59页

作者：徐敬堂唐永芬

Fengjiu Yi(Model FJY - 1) is a patent medical and health instrument newly developed by the authors. It incorporates the drug action and physiotherapy into an integral whole, exerting comprehensive regulation and it is an effective therapeutic method. In the present paper, 300 cases of exhaustion syndrome were all cured by the instrument after 7 - 17 sessions of treatment.

关键词： Model FJY-1 Fengjiu Yi Fengjiu therapy exhaustion syndrome

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Knock down of miR-15a/16 attenuates glioma progression by blocking tumor infiltrated T cell exhaustion in mice model

Knock down of miR-15a/16 attenuates glioma progression by bl...

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第十一届全国免疫学学术大会

作者： Jiao Yang Feifei Luo Ronghua Liu Yiwei Chu Department of Immunology School of Basic Medical Sciences Fudan University

Objective:Mi R-15a/16 has been considered as a direct tumor suppressor in many cancers,including breast cancer,colon cancer and glioma,by regulating cancer cells growth,proliferation and *** R-15a/16 also acts as an immune regulator in physiological and inflammatory conditions,impacting macrophage phagocytosis and NK *** study was focused on the role of mi R-15a/16 in tumor infiltrated T cells.

关键词： mi R-15a/16 glioma T cell exhaustion

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Neutrophils as key regulators of tumor immunity that restrict immune checkpoint blockade in liver cancer

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Cancer Biology & Medicine 2023年第6期20卷 421-437页

作者： Mei Feng Fangyanni Wang Xinyu Liu Tingting Hao Ning Zhang Mi Deng Yisheng Pan Ruirui Kong Translational Cancer Research Center Peking University First HospitalBeijing 100034China Division of General Surgery Peking University First HospitalBeijing 100034China International Cancer Institute Peking University Health Science CenterBeijing 100191China Yunnan Baiyao Group Kunming 650500ChinaDivision of General SurgeryPeking University First HospitalBeijing 100034China

Objective:Liver cancer is a deadly malignancy associated with high mortality and *** than 20%of patients with advanced liver cancer respond to a single anti-PD-1 *** high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely ***:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor *** ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T *** roles of neutrophils,T cells,and NK cells were validated through antibody-mediated *** efficacy of the combination of neutrophil depletion and ICB was ***:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 *** of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor ***,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G ***,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor ***:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.

关键词： Liver cancer neutrophil PD-1,CD8^(+)T cell exhaustion

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