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

Science. 2022 Sep 30;377(6614):1519-1529. doi: 10.1126/science.abj5104. Epub 2022 Sep 29.

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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • Carcinogenesis* / genetics
  • Carcinogenesis* / metabolism
  • Gain of Function Mutation
  • Glutarates* / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Isocitrate Dehydrogenase* / genetics
  • Isocitrate Dehydrogenase* / metabolism
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • L-Lactate Dehydrogenase / metabolism
  • Mice
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / metabolism

Substances

  • Glutarates
  • alpha-hydroxyglutarate
  • Interferon-gamma
  • L-Lactate Dehydrogenase
  • Isocitrate Dehydrogenase
  • IDH1 protein, human