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.
Subject(s)
Glutarates/metabolism , Immunity , T-Lymphocytes/immunology , Adenosine Triphosphate/metabolism , Animals , Apoptosis , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Calcium/metabolism , Cell Line, Tumor , Cell Proliferation , Glioma/genetics , Glioma/immunology , Humans , 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 TransductionABSTRACT
Adult and fetal haematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron-sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anaemia and prenatal death. RISP-null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP-null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation associated with increases in 2-hydroxyglutarate (2HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence concomitant with severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.
