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Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion

Published inNature Immunology
Publication date2020
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.

Affiliation Not a UNIGE publication
Citation (ISO format)
YU, Yi-Ru et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. In: Nature Immunology, 2020. doi: 10.1038/s41590-020-0793-3
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ISSN of the journal1529-2908
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Creation10/07/2020 11:33:00 PM
First validation10/07/2020 11:33:00 PM
Update time03/15/2023 10:44:05 PM
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