EZH2 linked to immunotherapy resistance in melanoma

In a paper published in Cell Reports, researchers at the University of Zurich and University Hospital Zurich showed that cancer immunotherapy increases levels of the epigenetic modifier enhancer of zeste homolog 2 (EZH2) in melanoma cells, which subsequently reduces response to immunotherapies. The team found that inhibition of the enzyme reversed immunotherapy resistance and suggested that EZH2 inhibition could be combined with immunotherapy to treat cancer.

In mouse models of melanoma, anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4; CTLA4; CD152) or IL-2 immunotherapy led to increased EZH2 expression in melanoma cells and reduced antigen presentation and immunogenicity compared to vehicle. In the mice, the team used short hairpin RNA against EZH2 or the EZH2 inhibitor GSK503 from GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) and showed that inactivating the protein restored melanoma immunogenicity. Furthermore, a combination of EZH2 inhibition plus immunotherapy led to more pronounced reductions in tumor volume compared to each treatment alone. The scientists also showed that a combination of EZH2 inhibition plus IL-2 immunotherapy suppressed the PD-1/PD-L1 axis in mice...