d-2HG Inhibits Effector T Cells by Altering Metabolic Programming

Metabolic byproducts of tricarboxylic acid cycle enzyme mutations known as “oncometabolites” can act as signaling molecules and drive disease progression. In cancers with gain-of-function mutations in IDH1 and IDH2, increases in d-2-hydroxyglutarate (d-2HG) cause a slow accumulation of epigenetic alterations within cancer cells that drive oncogenic transformation. However, the tumor cell–extrinsic function of d-2HG within the tumor microenvironment has not been well defined. Here, Notarangelo and colleagues demonstrate that extracellular d-2HG inhibits CD8⁺ T-cell proliferation, cytotoxicity, and IFNy signaling by significantly altering T-cell metabolism. Treatment with pathophysiological levels of d-2HG, but not its enantiomer l-2HG, rapidly caused defects in activated CD8⁺ T-cell proliferation, degranulation, and IFNy expression, which, in turn, impaired antitumor activity. The cell-extrinsic effects of d-2HG were found to be transient, indicating that the underlying mechanism is outside of its known cell-intrinsic role as an epigenetic regulator. Through the performance of steady-state metabolomics, glucose tracing experiments, and recombinant protein biochemistry, d-2HG was found to directly inhibit lactate dehydrogenase (LDH) activity, which, in turn, blocks glycolysis and alters NAD(H) balance. Investigation into the impact of d-2HG on mitochondrial function and ATP generation revealed that d-2HG uptake leads to hyperpolarization of the mitochondrial membrane and subsequently increases oxidative phosphorylation in a reversible and rapid manner. In order to evaluate the contribution of LDH inhibition to the phenotypes observed following d-2HG uptake in CD8⁺ T cells, treatment with two independent LDH inhibitors was conducted, and results indicated that this treatment recapitulated the impact of d-2HG treatment on CD8⁺ T-cell metabolism, proliferation, IFNy signaling, and cytotoxicity. Furthermore, evaluation of human single-cell RNA sequencing data and tissue sections from IDH-mutant and wild-type patients revealed similarly altered metabolic and cytotoxic programs in patients with IDH mutations along with high d-2HG concentrations. Altogether, this work demonstrates that extracellular d-2HG has functional activity, unique from its tumor cell–intrinsic role, that suppresses antitumor immunity.

Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8⁺ T cell function. Science 2022;377:1519–29.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.