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

Fiche publication

Date publication

septembre 2026

Journal

Molecular cancer

Auteurs

Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel , Dr DUTEIL Delphine

Tous les auteurs :
Peñarando J, Willmann D, Sum M, Jia Y, Berlin C, Braun LM, Chen Z, Urban S, Jung M, Duteil D, Metzger D, Gratzke C, Zeiser R, Greschik H, Schüle R, Metzger E

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42760560

Résumé

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.