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

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.

SUBMITTER: Notarangelo G

PROVIDER: S-EPMC9629749 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Oncometabolite d-2HG alters T cell metabolism to impair CD8<sup>+</sup> T cell function.

Notarangelo Giulia G Spinelli Jessica B JB Perez Elizabeth M EM Baker Gregory J GJ Kurmi Kiran K Elia Ilaria I Stopka Sylwia A SA Baquer Gerard G Lin Jia-Ren JR Golby Alexandra J AJ Joshi Shakchhi S Baron Heide F HF Drijvers Jefte M JM Georgiev Peter P Ringel Alison E AE Zaganjor Elma E McBrayer Samuel K SK Sorger Peter K PK Sharpe Arlene H AH Wucherpfennig Kai W KW Santagata Sandro S Agar Nathalie Y R NYR Suvà Mario L ML Haigis Marcia C MC

Science (New York, N.Y.) 20220929 6614

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<sup>+</sup> T cells and altered their m ...[more]

PMID: 36173860

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Project description:BackgroundD-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored.MethodsWe applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m6A) modification. RNA pull-down assays were further applied to identify the reader that could specifically recognize the m6A modification on angiopoietin like 4 (ANGPTL4) mRNA and RNA immunoprecipitation was used to confirm the findings.ResultsWe found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m6A RNA modifications in TNBC cells, notably upregulating m6A modification on ANGPTL4 mRNA, which was mediated by the inhibition of Fat-mass and obesity-associated protein (FTO), resulting in increased recognition of m6A-modified ANGPTL4 by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), thereby promoting the enhanced translation of ANGPTL4. As a secretory protein, ANGPTL4 subsequently activated the integrin-mediated JAK2/STAT3 signaling cascade in TNBC cells through autocrine signaling. Notably, the knockdown of ANGPTL4 or treatment with GLPG1087 (an integrin antagonist) significantly reduced D-2HG-induced proliferation and metastasis in TNBC cells. Additionally, ANGPTL4 was found to promote macrophage M2 polarization within the tumor microenvironment via paracrine signaling, further driving TNBC progression. The association of ANGPTL4 with poor prognosis in TNBC patients underscores its clinical relevance.ConclusionsOur study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m6A/ANGPTL4/integrin axis can serve as a promising therapeutic target for TNBC patients.

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

Publications

Oncometabolite d-2HG alters T cell metabolism to impair CD8<sup>+</sup> T cell function.

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

Publications

Oncometabolite d-2HG alters T cell metabolism to impair CD8<sup>+</sup> T cell function.

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OmicsDI is part of the ELIXIR infrastructure

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