PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity

Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene -targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8+ T cell -mediated anti -tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifng)-induced MHC-I expression, thus dampening CD8+ T cell -mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifng-induced MHC-I expression through elevated STAT1 expression and activation, while re -introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti -PD -1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti -tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies.