GSE161909
Chromatin accessibility in MC38/gp100 cells after type I PRMT inhibitor treatment
Immunotherapies have produced dramatic responses in reducing tumor growth and prolonging overall survival to unprecedented rates in melanoma, lung cancer, renal cancer and mismatch repair deficient colon cancer patients. Despite approvals for immune checkpoint inhibitors in a wide range of cancers, the majority of patients' relapse following initial response to immunotherapy or fail to respond altogether. These failures can be attributed to an insufficient immune response against tumors and/or mechanisms co-opted by tumor cells to produce a suppressive tumor microenvironment. Therefore, identification of combination strategies to enhance the response rates of immunotherapies to a broader patient population are the current subject of intensive basic and clinical research. Type I PRMTs have been described as regulators of immune response pathways in several cell types by direct arginine methylation on specific substrates, as well as through indirect mechanisms. Recent work has suggested that arginine methylation may have a role in tumor immunity, yet these roles remain poorly understood. Using the skin cutaneous melanoma (SKCM) TCGA dataset, we show that increased expression of Type I PRMTs is associated with poor clinical response and decreased immune infiltration in melanoma patients. Through a series of preclinical tumor models, we demonstrate that inhibition of Type I PRMTs can increase hallmarks of an inflamed tumor microenvironment and sensitivity to inhibition of the PD-(L)1 signaling axis. Accordingly, Type I PRMT inhibition synergizes with immune checkpoint blockade to induce durable and effective antitumor responses in an array of immunocompetent tumor models. These data provide a rationale to combine Type I PRMT inhibitors with checkpoint blockade to maximize clinical benefit in cancer patients. Overall design: Chromatin accessibility profile of MC38/gp100 cells treated with DMSO or 1uM GSK3368712 for 5 days