%0 Journal Article
%A Wenes, Mathias
%A Jaccard, Alison
%A Wyss, Tania
%A Maldonado-Pérez, Noelia
%A Teoh, Shao Thing
%A Lepez, Anouk
%A Renaud, Fabrice
%A Franco, Fabien
%A Waridel, Patrice
%A Yacoub Maroun, Céline
%A Tschumi, Benjamin
%A Dumauthioz, Nina
%A Zhang, Lianjun
%A Donda, Alena
%A Martín, Francisco
%A Migliorini, Denis
%A Lunt, Sophia Y
%A Ho, Ping-Chih
%A Romero, Pedro
%T The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
%D 2022
%U http://hdl.handle.net/10668/22118
%X 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.
%K T cell memory
%K chimeric antigen receptor T cell therapy
%K immunometabolism
%K mitochondrial pyruvate carrier
%K tumor-infiltrating lymphocyte metabolism
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