Repositori URV

Identifier: imarina:9282881

Handle: https://hdl.handle.net/20.500.11797/imarina9282881

Authors:
Notarangelo GSpinelli JBPerez EMBaker GJKurmi KElia IStopka SABaquer GLin JRGolby AJJoshi SBaron HFDrijvers JMGeorgiev PRingel AEZaganjor EMcBrayer SKSorger PKSharpe AHWucherpfennig KWSantagata SAgar NYRSuvà MLHaigis MC

Abstract:
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.