RT Journal Article
T1 The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
A1 Wenes, Mathias
A1 Jaccard, Alison
A1 Wyss, Tania
A1 Maldonado-Pérez, Noelia
A1 Teoh, Shao Thing
A1 Lepez, Anouk
A1 Renaud, Fabrice
A1 Franco, Fabien
A1 Waridel, Patrice
A1 Yacoub Maroun, Céline
A1 Tschumi, Benjamin
A1 Dumauthioz, Nina
A1 Zhang, Lianjun
A1 Donda, Alena
A1 Martín, Francisco
A1 Migliorini, Denis
A1 Lunt, Sophia Y
A1 Ho, Ping-Chih
A1 Romero, Pedro
K1 T cell memory
K1 chimeric antigen receptor T cell therapy
K1 immunometabolism
K1 mitochondrial pyruvate carrier
K1 tumor-infiltrating lymphocyte metabolism
AB 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.
YR 2022
FD 2022-04-21
LK http://hdl.handle.net/10668/22118
UL http://hdl.handle.net/10668/22118
LA en
DS RISalud
RD Apr 10, 2025