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Yu, Yi-Ru; Imrichova, Hana; Wang, Haiping; Chao, Tung; Xiao, Zhengtao; Gao, Min; Rincon-Restrepo, Marcela; Franco, Fabien; Genolet, Raphael; Cheng, Wan-Chen; Jandus, Camilla; Coukos, George; Jiang, Yi-Fan; Locasale, Jason W; Zippelius, Alfred; Liu, Pu-Ste; Tang, Li; Bock, Christoph; Vannini, Nicola; Ho, Ping-Chih
Nature immunology, 12/2020, Volume: 21, Issue: 12Journal Article
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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