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Science ; 377(6614): 1519-1529, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36173860

RESUMO

Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.


Assuntos
Linfócitos T CD8-Positivos , Carcinogênese , Glutaratos , Isocitrato Desidrogenase , Neoplasias , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Mutação com Ganho de Função , Glutaratos/metabolismo , Humanos , Interferon gama/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo
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