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http://ir.nhri.org.tw/handle/3990099045/13007
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| Title: | Disturbed mitochondrial dynamics in CD8(+)TILs reinforce T cell exhaustion |
| Authors: | 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 |
| Contributors: | Institute of Cellular and Systems Medicine |
| Abstract: | 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. |
| Date: | 2020-12 |
| Relation: | 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 |
| Appears in Collections: | [劉卜慈] 期刊論文
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| ISI000575347200002.pdf | | 9241Kb | Adobe PDF | 387 | View/Open |
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