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Professor Yang Shi’s group uses combination therapy to eradicate tumours that previously responded poorly to immunotherapy

Immunotherapy has shown remarkable efficacy against a range of cancers. One approach, termed immune checkpoint blockade therapy, blocks an inhibitory immune receptor called PD-1 to take the brakes off the immune system and allow it to kill cancer cells. However, despite this success, anti-PD-1 therapy is ineffective in the majority of cancer patients.

Research is underway to discover strategies that can overcome tumour resistance to immunotherapy. A promising avenue for further investigation is the manipulation of epigenetic regulators. Epigenetic regulators influence the expression of genes without changing the underlying DNA sequence. They can dampen the response of the immune system and their inhibition has been shown to enhance the response to anti-PD-1 treatment. However, because epigenetic regulators are involved in several aspects of the anti-tumour immune response, inhibiting them can result in potentially opposing effects, with the result of little or no overall benefit.

In this paper published in the journal Cancer Discovery, Professor Yang Shi and his laboratory explore the opposing effects of inhibiting one such epigenetic regulator, LSD1. Using mouse and tumour cell models, they show that when LSD1 is repressed, there is a greater immune cell infiltration into the tumour but this is counteracted by the increased production of a cell regulatory protein called TGF-β that suppresses the ability of these 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. This combination treatment led to eradication of these previously resistant tumours and long-lasting protection from tumour re-challenge, making it a promising future strategy for increasing the efficacy of this important class of cancer treatment.

 

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