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

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. WucherpfennigSandro Santagata, Nathalie Y.R. Agar, Mario L. Suvà, Marcia C. Haigis

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1519-1529
Number of pages11
JournalScience (New York, N.Y.)
Volume377
Issue number6614
DOIs
StatePublished - Sep 30 2022

ASJC Scopus subject areas

  • General

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