Disturbed mitochondrial dynamics in CD8<sup>+</sup> TILs reinforce T cell exhaustion.

Détails

ID Serval
serval:BIB_89908ED24FA7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Disturbed mitochondrial dynamics in CD8<sup>+</sup> TILs reinforce T cell exhaustion.
Périodique
Nature immunology
Auteur(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., Jiang Y.F., Locasale J.W., Zippelius A., Liu P.S., Tang L., Bock C., Vannini N., Ho P.C.
ISSN
1529-2916 (Electronic)
ISSN-L
1529-2908
Statut éditorial
Publié
Date de publication
12/2020
Peer-reviewed
Oui
Volume
21
Numéro
12
Pages
1540-1551
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
Pubmed
Web of science
Création de la notice
09/10/2020 11:44
Dernière modification de la notice
23/11/2020 6:24
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