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