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.

Differentiating Inhibition Selectivity and Binding Affinity of Isocitrate Dehydrogenase 1 Variant Inhibitors

“…In addition to wild-type (wt) activity, i.e., NADP + -coupled oxidation of isocitrate to 2-oxoglutarate (2OG), the homodimeric IDH1/2 variants have a neomorphic activity, i.e., NADPH-coupled reduction of the wt product 2OG to 2-hydroxyglutarate (2HG) (Scheme ). Elevated 2HG levels are proposed to promote tumorigenesis and suppress antitumor immunity . Inhibitors of IDH1/2 variants (mIDH1/2) efficiently reduce 2HG levels in vivo, alter cellular metabolism, and are useful for AML treatment, as shown by pioneering studies with Ivosidenib and Enasidenib; mIDH inhibitors are also being explored for treatments of other cancer types, including solid tumors .…”

“… 3 Elevated 2HG levels are proposed to promote tumorigenesis 3 and suppress antitumor immunity. 4 Inhibitors of IDH1/2 variants (mIDH1/2) efficiently reduce 2HG levels in vivo, alter cellular metabolism, and are useful for AML treatment, as shown by pioneering studies with Ivosidenib and Enasidenib; mIDH inhibitors are also being explored for treatments of other cancer types, including solid tumors. 5 Despite their diverse structures and origins, there is extensive crystallographic evidence that most reported mIDH inhibitors do not bind at the active site but instead bind at the IDH homodimer interface which involves an α-helical bundle 6 − 9 ( Figures 1 and S1 ).…”

Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2

“…In this regard, it is notable that ( 3S )-hydroxy-2-oxobutanoic acid, the transamination product of threonine, has recently been proposed as a substrate of IDH variants based on metabolomic studies ( 59 ). It will also be of interest to explore whether the reduced 2OG derivatives have a similar effect on cancer progression as identified for 2HG itself ( 4 , 25 ).…”

“…Considering the widespread abundance of 2-oxoacid and alcohol couples in cells, it seems likely that cancer-associated IDH1/2 variants affect metabolism in ways other than catalyzing the reduction of 2OG to 2HG. For example, recent evidence suggests that extracellular 2HG is taken up by CD8-positive T cells in which it inhibits lactate dehydrogenase, thus altering glucose metabolism resulting in decreased proliferation, decreased cytokine production, and a decreased ability to kill target cells ( 25 ). Some 2-oxoacid and 2OG derivatives have been shown to be poor substrates of pig and rat WT IDH (obtained from homogenized pig heart and rat liver, respectively) ( 13 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ); however, the substrate selectivity of human oncogenic IDH1/2 variants with 2-oxoacids other than 2OG has not yet been investigated.…”

The Network Zoo: a multilingual package for the inference and analysis of gene regulatory networks

“…Finally, motivated by recent findings implicating oncometabolites in altering the epigenetic landscape in cancer [53], we analyzed oncometabolite 2-hydroxglutarate (2HG) levels because it has been shown to induce the hypermethylator phenotype in glioma and acute myeloid leukemia by inhibiting histone demethylases [54]. To identify TFs that are associated with 2HG epigenetic regulation, we computed correlations between TF targeting and 2HG levels across all CCLE cell lines using DRAGON (Fig.…”