Researchers led by Ludwig Harvard’s Marcia Haigis identified a previously unknown metabolic mechanism by which tumor cells can suppress T cell attack. She and her colleagues reported in Science in late September that D-2-hydroxyglutarate (D2HG), a metabolite that accumulates in cancer cells that have mutations in an enzyme named isocitrate dehydrogenase (IDH), can impair glucose metabolism in mouse T cells and suppress anti-tumor immunity. IDH mutations are found in about 3.5% of cancers, including brain and blood cancers. The researchers found that when taken up by T cells, D2HG inhibits the activity of an enzyme involved in glucose metabolism known as lactate dehydrogenase. This drives a metabolic program that inhibits the proliferation of T cells, their production of immunostimulatory factors called cytokines and their ability to kill cancer cells—effects that are reversible with the withdrawal of D2HG. The molecular signature associated with these effects was recapitulated in samples taken from patients with IDH1-mutant brain tumors. In these tumors, areas with high concentrations of D2HG also had a sparse presence of cytotoxic T cells, and vice versa, supporting the findings made in mice. The findings suggest that the oncometabolite, which is already known to promote cancer growth, may also help tumors resist immune clearance.
Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function
Science, 2022 September 29