Researchers are exploring multiple strategies to overcome resistance to anti-PD-1 checkpoint blockade immunotherapy, which is only effective against a limited subset of patients and cancer types. These include the manipulation of epigenetic regulators, which control the expression of genes. But perturbation of these enzymes can have opposing effects on various aspects of the anti-tumor response, resulting in dampened or no overall benefit. Ludwig Oxford’s Yang Shi and colleagues reported in Cancer Discovery in March their examination of the opposing effects of inhibiting one such epigenetic regulator, LSD1. They showed in mouse and cell models that suppressing LSD1 boosts killer T cell infiltration into tumors. But this effect is counteracted by the increased production of a signaling protein called TGF-β that suppresses the activity of these cells. Depleting both LSD1 and TGF-β during anti-PD-1 therapy increased T cell infiltration and improved their function, eradicating tumors that were previously resistant to checkpoint blockade and establishing an immune memory of the tumor in the mice. Yang and his coauthors suggest combining LSD1 inhibition with TGF-β and PD-1 blockade could expand the utility and efficacy of the immunotherapy.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).