PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade

Abstract

Despite the success of immune checkpoint inhibitor (ICI) therapy in different cancers, resistance and relapses are frequent. Thus, combination therapies are expected to enhance response rates and overcome resistance to ICIs. Herein, we report that combining protein arginine methyltransferase 7 (PRMT7) inhibition with ICIs triggers a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing tumor immune cell infiltration. Consistently, TCGA database analysis showed an inverse correlation between PRMT7 expression and T cell infiltration in human melanomas. Mechanistically, we show that PRMT7 has a two-prong effect on melanoma tumor immunity. On one hand, it serves as a coactivator of IRF-1 for PD-L1 expression by upregulating promoter H4R3me2s levels in melanoma cells. Next, PRMT7 prevents repetitive element expression to avoid intracellular dsRNA accumulation or viral mimicry. PRMT7 deletion resulted in increased endogenous retroviral elements (ERVs), dsRNA, and genes implicated in interferon activation, antigen presentation and chemokine signaling. Our findings identify PRMT7 as factor used by melanoma to evade anti-tumor immunity and define the therapeutic potential of PRMT7 alone or in combination with PD-(L)1 blockade to enhance ICI efficiency.