Abstract
The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Adenosine Triphosphate / metabolism
- Animals
- Apoptosis
- Brain Neoplasms / genetics
- Brain Neoplasms / immunology
- Calcium / metabolism
- Cell Line, Tumor
- Cell Proliferation
- Glioma / genetics
- Glioma / immunology
- Glutarates / metabolism*
- Humans
- Immunity*
- Isocitrate Dehydrogenase / genetics
- Isocitrate Dehydrogenase / metabolism
- Lymphocyte Activation / immunology
- Mice, Inbred C57BL
- Mutation / genetics
- NFATC Transcription Factors / metabolism
- Paracrine Communication
- Polyamines / metabolism
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Receptors, Antigen, T-Cell / metabolism
- Signal Transduction
- T-Lymphocytes / immunology*
Substances
- Glutarates
- NFATC Transcription Factors
- Polyamines
- RNA, Messenger
- Receptors, Antigen, T-Cell
- alpha-hydroxyglutarate
- Adenosine Triphosphate
- Isocitrate Dehydrogenase
- IDH1 protein, human
- Calcium