Cell Metab. 2022 Apr 18. pii: S1550-4131(22)00127-9. [Epub ahead of print]
Mathias Wenes,
Alison Jaccard,
Tania Wyss,
Noelia Maldonado-Pérez,
Shao Thing Teoh,
Anouk Lepez,
Fabrice Renaud,
Fabien Franco,
Patrice Waridel,
Céline Yacoub Maroun,
Benjamin Tschumi,
Nina Dumauthioz,
Lianjun Zhang,
Alena Donda,
Francisco Martín,
Denis Migliorini,
Sophia Y Lunt,
Ping-Chih Ho,
Pedro Romero.
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.
Keywords: T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism