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

• Published in: Science (American Association for the Advancement of Science) Vol. 377; no. 6614; pp. 1519 - 1529
• Main 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., Suvà, Mario L., Haigis, Marcia C.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 30.09.2022
• Subjects: Animals; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell proliferation; Cytokines; Dehydrogenase; Gain of Function Mutation; Glucose metabolism; Glutarates - metabolism; Humans; Immunosuppressive agents; Interferon-gamma - metabolism; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - antagonists & inhibitors; L-Lactate Dehydrogenase - metabolism; Lactate dehydrogenase; Lactic acid; Lymphocytes; Lymphocytes T; Metabolites; Mice; Mutation; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abj5104

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. Cancer-causing mutations in isocitrate dehydrogenase cause accumulation of the metabolite d -2-hydroxyglutarate ( d -2HG). Notarangelo et al . showed that such high concentrations of d -2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells (see the Perspective by Nathan). Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. The authors propose that in addition to its known cell-autonomous cancer-promoting effects, d -2HG may also have immunosuppressive activity. —LBR Excess metabolite from cancer cells may hinder antitumor immunity.