Cancer cells favor a process for extracting energy from sugar known as glycolysis that most healthy cells only deploy when oxygen is in short supply. This phenomenon—the Warburg effect—depletes glucose in the tumor microenvironment, depriving anti-tumor T cells of a nutrient they too require to function effectively. Targeting cancer cell glycolysis would be a great way to improve immunotherapy, but it must be done without compromising T cell functionality. One candidate for such targeting is an enzyme called lactate dehydrogenase (LDH) that plays a key role in glycolysis and is expressed at much higher levels in tumor cells than in T cells. Researchers led by Jedd Wolchok and Taha Merghoub, co-directors of the Ludwig Collaborative Laboratory at Weill Cornell, Ludwig MSK alumnus Roberta Zappasodi and first-author Svena Verma reported in The Journal of Clinical Investigation in September that treatment with an LDH inhibitor decreases tumor cell glucose uptake and proliferation but has exactly the opposite effect on tumor-infiltrating T cells in mice. The treatment pumps up glucose levels in the microenvironment, enhances T cell killing of cancer cells and inhibits immunosuppressive regulatory T cells (Tregs) in culture. Combined with immune checkpoint blockade therapy, it effectively controls melanoma and colon cancer progression in mice by boosting effector T cell infiltration and activation while destabilizing Tregs—suggesting a new combination therapy.
Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models
The Journal of Clinical Investigation, 2024 September 3