KMT9 drives T cell exclusion and dysfunction by promoting PMN-MDSCs infiltration and ARG1 expression in prostate cancer

Immunotherapy has emerged as a revolutionary therapeutic approach to treat cancer showing remarkable clinical responses. However, its efficacy in solid tumours such as prostate cancer (PCa) remains very limited due to a highly immunosuppressive tumour immune microenvironment (TIME) that hampers cytotoxic T cell infiltration and activity. Here, we show that lysine methyltransferase 9 (KMT9) governs the formation of an immunosuppressive TIME in PCa. KMT9 regulates the expression of tumour-secreted myeloid-attracting C-X-C motif chemokine receptor 2 (CXCR2) ligands such as C-X-C motif chemokine ligand 5 (CXCL5) thereby promoting the infiltration of immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within tumours. These changes collectively result in decreased activation and exclusion of cytotoxic T cells from tumour glands. Furthermore, we demonstrate that KMT9 confers tumour cell-resistance to T cell cytotoxicity by regulating expression of arginase 1 (ARG1). Accordingly, KMT9α ablation results in inhibition of prostate tumour growth accompanied by a massive reduction of PMN-MDSC recruitment and a significant increase in cytotoxic T cell activation and infiltration of the prostate tumour glands. Together, we uncovered KMT9 as a regulator of immune evasion that promotes an immune-excluded TIME in prostate tumours. Furthermore, our findings establish KMT9 as a therapeutic target to reprogram the immunosuppressive landscape and potentially improve the clinical efficacy of current immunotherapies.