Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
Yi-Ru Yu, Hana Imrichova, Haiping Wang, Tung Chao, Zhengtao Xiao, Min Gao, Marcela Rincon-Restrepo, Fabien Franco, Raphael Genolet, Wan-Chen Cheng, Camilla Jandus, George Coukos, Yi-Fan Jiang, Jason W. Locasale, Alfred Zippelius, Pu-Ste Liu, Li Tang, Christoph Bock, Nicola Vannini, Ping-Chih Ho
Abstract
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.
Journal
Nature Immunology
Model
In Vitro
Impact Factor
20.479