Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
Journal
Nature Immunology
Journal Volume
21
Journal Issue
12
Pages
1540-1551
Date Issued
2020
Author(s)
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.
Locasale, J.W.
Zippelius, A.
Liu, P.-S.
Tang, L.
Bock, C.
Vannini, N.
Ho, P.-C.
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.
SDGs
Type
journal article