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

Identifier:  imarina:9282881

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

Authors:  Notarangelo, Giulia; Spinelli, Jessica B; Perez, Elizabeth M; Baker, Gregory J; Kurmi, Kiran; Elia, Ilaria; Stopka, Sylwia A; Baquer, Gerard; Lin, Jia-Ren; Golby, Alexandra J; Joshi, Shakchhi; Baron, Heide F; Drijvers, Jefte M; Georgiev, Peter; Ringel, Alison E; Zaganjor, Elma; McBrayer, Samuel K; Sorger, Peter K; Sharpe, Arlene H; Wucherpfennig, Kai W; Santagata, Sandro; Agar, Nathalie Y R; Suva, Mario L; Haigis, Marcia C

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.