A study led by Ludwig Lausanne’s Alison Jaccard, Ping-Chih Ho and their University of Lausanne colleagues Mathias Wenes and Pedro Romero uncovered an unexpected link between T cell metabolism, regulation of gene expression, persistence and functional efficacy that may be exploited using existing drugs to enhance cancer immunotherapy. The researchers reported in a September issue of Nature that CD8+ T cells, like cancer cells, employ reductive carboxylation to generate citrate—a metabolite required to make membranes—from the amino acid glutamine. But blocking this process genetically or with drugs known as IDH2 inhibitors does not compromise their effector function or proliferation. Rather, it turns them into functionally potent memory T cells. This, the researchers showed, is because it forces the T cells to activate compensatory metabolic pathways, altering the profile of metabolites in the cells and boosting some that inhibit the epigenetic enzyme KDM5. The resulting epigenetic changes open up access to genes in the T cells’ chromosomes that define memory T cells, triggering their transformation. In the absence of IDH2 inhibition, those genes are kept under wraps, bolstering their typical terminally exhausted CD8+ T cell identity. The researchers demonstrated that chimeric antigen receptor (CAR) T cells cultured in the presence of IDH2 inhibitors show enhanced anti-tumor activity in mouse models of melanoma, leukemia and multiple myeloma.
Reductive carboxylation epigenetically instructs T cell differentiation
Nature, 2023 September 20