Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion.
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.
Yu, Y-R; Imrichova, H; Wang, H; Chao, T; Xiao, Z; Gao, M; Rincon-Restrepo, M; Franco, F; Genolet, R; Cheng, W-C; Jandus, C; Coukos, G; Jiang, Y-F; Locasale, JW; Zippelius, A; Liu, P-S; Tang, L; Bock, C; Vannini, N; Ho, P-C
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