TY - JOUR TI - Disturbed mitochondrial dynamics in CD8 + TILs reinforce T cell exhaustion AU - Yu, Yi-Ru AU - Imrichova, Hana AU - Wang, Haiping AU - Chao, Tung AU - Xiao, Zhengtao AU - Gao, Min AU - Rincon-Restrepo, Marcela AU - Franco, Fabien AU - Genolet, Raphael AU - Cheng, Wan-Chen AU - Jandus, Camilla AU - Coukos, George AU - Jiang, Yi-Fan AU - Locasale, Jason W. AU - Zippelius, Alfred AU - Liu, Pu-Ste AU - Tang, Li AU - Bock, Christoph AU - Vannini, Nicola AU - Ho, Ping-Chih T2 - Nature Immunology AB - 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. DA - 2020/10/05/ PY - 2020 DO - 10.1038/s41590-020-0793-3 DP - www.nature.com SP - 1 EP - 12 LA - en SN - 1529-2916 UR - https://www.nature.com/articles/s41590-020-0793-3 Y2 - 2020/10/05/23:31:45 ER -