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Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.


Notarangelo G , Spinelli BJ , Perez ME , Baker JG , Kurmi K , Elia I , Stopka AS , Baquer G , Lin J , Golby JA , Joshi S , Baron FH , Drijvers MJ , Georgiev P , Ringel EA , Zaganjor E , McBrayer KS , Sorger KP , Sharpe HA , Wucherpfennig WK , Santagata S , Agar YRN , Suvà LM , Haigis CM . Science. 2022 9 30; ().


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.