The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function.
Cell Metab
; 34(5): 731-746.e9, 2022 05 03.
Article
em En
| MEDLINE
| ID: mdl-35452600
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.
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Base de dados:
MEDLINE
Assunto principal:
Transportadores de Ácidos Monocarboxílicos
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Células T de Memória
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article