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