The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
ddc:616
Monocarboxylic Acid Transporters Physiology immunometabolism T cell memory Cell Biology Mitochondrial Membrane Transport Proteins mitochondrial pyruvate carrier Mitochondria Memory T Cells chimeric antigen receptor T cell therapy immune system diseases tumor-infiltrating lymphocyte metabolism Pyruvic Acid Lactates Molecular Biology |
| Zdroj: | Cell metabolism (2022) |
| ISSN: | 1932-7420 1550-4131 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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