國家衛生研究院 NHRI:Item 3990099045/13007
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    题名: Disturbed mitochondrial dynamics in CD8(+)TILs reinforce T cell exhaustion
    作者: Yu, YR;Imrichova, H;Wang, HP;Chao, T;Xiao, ZT;Gao, M;Rincon-Restrepo, M;Franco, F;Genolet, R;Cheng, WC;Jandus, C;Coukos, G;Jiang, YF;Locasale, JW;Zippelius, A;Liu, PS;Tang, L;Bock, C;Vannini, N;Ho, PC
    贡献者: Institute of Cellular and Systems Medicine
    摘要: Ho and colleagues report that mitochondrial dysfunction and impaired mitophagy triggered by the tumor microenvironment lead to subsequent epigenetic changes and cause permanent T cell exhaustion and dysfunction. The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
    日期: 2020-12
    關聯: Nature Immunology. 2020 Dec;21(12):1540-1551.
    Link to: http://dx.doi.org/10.1038/s41590-020-0793-3
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1529-2908&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000575347200002
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85092085834
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