Targeting PRC1 Suppresses Double Negative Prostate Cancer Metastasis by Inhibiting Stemness and Reversing Immune Suppression

The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex-1 drives the colonization of the bones and visceral organs in Double-Negative Prostate Cancer (DNPC). In vivo genetic screening identifies CCL2 as the top pro-metastatic gene induced by PRC1. Mechanistic studies show that CCL2 governs self-renewal and induces the recruitment of M2-like TAMs and Tregs, thus coordinating metastasis initiation with the creation of a profoundly immunosuppressive and proangiogenic microenvironment. A novel catalytic inhibitor of PRC1 cooperates with checkpoint immunotherapy to reverse immunosuppression and neoangiogenesis and suppress metastatic outgrowth in genetically engineered transplantation models that mimic the pattern of human DNPC. These results reveal that PRC1 coordinates self-renewal with immune evasion at metastatic sites.