Cell Metab. 2022 Apr 18;S1550-4131(22)00127-9. doi: 10.1016/j.cmet.2022.03.013. Online ahead of print.
The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function
Mathias Wenes 1, Alison Jaccard 2, Tania Wyss 3, Noelia Maldonado-Pérez 4, Shao Thing Teoh 5, Anouk Lepez 6, Fabrice Renaud 3, Fabien Franco 2, Patrice Waridel 7, Céline Yacoub Maroun 3, Benjamin Tschumi 3, Nina Dumauthioz 3, Lianjun Zhang 8, Alena Donda 3, Francisco Martín 4, Denis Migliorini 9, Sophia Y Lunt 10, Ping-Chih Ho 2, Pedro Romero 11
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.
Keywords: T cell memory; chimeric antigen receptor T cell therapy; immunometabolism; mitochondrial pyruvate carrier; tumor-infiltrating lymphocyte metabolism.
- PMID: 35452600
- DOI: 10.1016/j.cmet.2022.03.013