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Scientific article
Open access
English

The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function

Published inCell metabolism
First online date2022-04-21
Abstract

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.

eng
Keywords
  • T cell memory
  • Chimeric antigen receptor T cell therapy
  • Immunometabolism
  • Mitochondrial pyruvate carrier
  • Tumor-infiltrating lymphocyte metabolism
Citation (ISO format)
WENES, Mathias et al. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. In: Cell metabolism, 2022. doi: 10.1016/j.cmet.2022.03.013
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ISSN of the journal1550-4131
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138downloads

Technical informations

Creation04/23/2022 2:14:00 PM
First validation04/23/2022 2:14:00 PM
Update time03/16/2023 6:26:46 AM
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