A combination therapy could overcome resistance to a checkpoint blockade

Ludwig Oxford’s Yang Shi and colleagues show that a triple combination therapy eradicates tumors in mice that previously responded poorly to anti-PD-1 therapy

March 15, 2021—Immunotherapy has shown remarkable efficacy against a range of cancers. One approach, checkpoint blockade therapy, targets an inhibitory immune receptor called PD-1 to boost the anti-cancer immune response. Despite its successes, however, anti-PD-1 therapy has proved ineffective in most cancer patients.

Researchers are exploring multiple strategies to overcome tumor resistance to checkpoint blockade, including the manipulation of epigenetic regulators, which control the expression of genes. Some epigenetic regulators have been shown to dampen anti-cancer immune responses, including those fired up by PD-1 blockade. But because epigenetic regulators are involved in several aspects of the anti-tumor immune response, inhibiting them can have opposing effects, resulting in little or no overall benefit.

In this paper published in the journal Cancer Discovery, Ludwig Oxford’s Yang Shi and his laboratory examined the opposing effects of inhibiting one such epigenetic regulator, LSD1. Using mouse and tumor cell models, they show that when LSD1 is repressed, there is greater immune cell infiltration into tumors. But this is counteracted by the increased production of a signaling protein called TGF-β that suppresses the ability of the infiltrating immune cells to kill cancer cells.

To tackle these conflicting effects, the team experimentally depleted both LSD1 and TGF-β during anti-PD-1 therapy and demonstrated a significant increase in immune cell infiltration, cytotoxicity and cancer-cell killing with the triple therapy. Combination treatment led to eradication of tumors previously resistant to checkpoint blockade and conferred long-lasting protection in the mice from tumor re-challenge. Shi and his colleagues suggest such “triple combination therapy” could be a promising strategy for treating certain tumors that resist PD-1 blockade.


You are now leaving Ludwig Cancer Research's website and are going to a website that is not operated by the association. We are not responsible for the content or availability of linked sites. Do you wish to continue?