In a February paper in Nature, researchers led by Ludwig MSK’s Taha Merghoub, Jedd Wolchok and former postdoc Roberta Zappasodi, now at Cornell, described a mechanism by which the immunotherapy CTLA-4 blockade can disable suppressive immune cells to aid the destruction of certain tumors. The researchers used a model system in which tumors are relatively less reliant on burning sugar through glycolysis. In a mouse model of glycolysis-deficient breast tumors, CTLA-4 blockade not only stimulated cancer-targeting T cells but also reprogramed regulatory T cells (Tregs), which suppress anti-cancer immune responses. CTLA-4 blockade extended the survival of mice in which tumors were surgically removed compared to identically treated mice implanted with glycolysis-competent tumors. The effect correlated with increased infiltration of T cells into tumors and the establishment of a strong immune memory of the cancer in the mice, and Tregs in responsive tumors had lost their suppressive ability and were producing interferon-γ and TNF-α, which are normally produced by killer T cells. The researchers showed that depletion of glucose in the microenvironment by tumor glycolysis reinforces the functional stability of Tregs and described the signaling that destabilizes Tregs in an environment rich in glucose following CTLA-4 blockade. They are now looking for drugs that can suppress glycolysis in tumors to test as therapies in combination with CTLA-4 blockade.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).