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

Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression of genes in the interferon pathway, antigen presentation, and chemokine signaling. PRMT7 deficiency or inhibition with SGC3027 in B16.F10 melanoma results in reduced DNMT expression, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs) causing their increased expression. PRMT7-deficient cells increase RIG-I and MDA5 expression with a reduction in the H4R3me2s repressive histone mark at their gene promoters. Our findings identify PRMT7 as a regulatory checkpoint for RIG-I, MDA5, and their ERV-double-stranded RNA (dsRNA) ligands, facilitating immune escape and anti-tumor T cell immunity to restrain tumor growth. [Display omitted] •PRMT7 negatively regulates cell intrinsic IFN pathway and antigen presentation•PRMT7 suppresses anti-tumoral immunity by inhibiting RIG-I and MDA5 expression•PRMT7 deletion induces viral mimicry through ERVs and dsRNA accumulation Srour et al. report that PRMT7 loss in melanoma increases immune cell infiltration and the sensitivity to immunotherapy. Mechanistically, PRMT7 loss activates retinoic acid-inducible gene I-like receptors (RLR) pathway. Genome-wide analysis shows that PRMT7 regulates the IFN pathway, antigen presentation, and chemokine signaling. Thus, inhibiting PRMT7 improves treatment outcomes in melanoma. PRMT7 deficiency in melanoma enhances sensitivity to immune checkpoint therapy.