线粒体
细胞生物学
粒体自噬
生物
表观遗传学
重编程
CD8型
细胞
癌症研究
自噬
免疫学
免疫系统
生物化学
细胞凋亡
基因
作者
Yi-Ru Yu,Hana Imrichová,Haiping Wang,Tung Chao,Zhao Xiao,Min Gao,Marcela Rincón-Restrepo,Fabien Franco,Raphaël Genolet,Wan-Chen Cheng,Camilla Jandus,George Coukos,Yi-Fan Jiang,Jason W. Locasale,Alfred Zippelius,Po–Tsun Liu,Li Tang,Christoph Bock,Nicola Vannini,Ping‐Chih Ho
出处
期刊:Nature Immunology
[Springer Nature]
日期:2020-10-05
卷期号:21 (12): 1540-1551
被引量:265
标识
DOI:10.1038/s41590-020-0793-3
摘要
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.
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