The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression

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Authors: Wenjing Su ; Hyun Ho Han ; Yan Wang ; Boyu Zhang ; Bing Zhou ; Yuanming Cheng ; Alekya Rumandla ; Sreeharsha Gurrapu ; Goutam Chakraborty ; Jie Su ; Guangli Yang ; Xin Liang ; Guocan Wang ; Neal Rosen ; Howard I Scher ; Ouathek Ouerfelli

MeSH: Adenocarcinoma / drug therapy ; Adenocarcinoma / immunology ; Adenocarcinoma / metabolism* ; Adenocarcinoma / secondary ; Animals ; Antineoplastic Agents, Immunological / pharmacology ; Antineoplastic Combined Chemotherapy Protocols / pharmacology ; Cell Movement* / drug effects ; Cell Self Renewal* / drug effects ; Chemokine CCL2 / genetics ; Chemokine CCL2 / metabolism* ; Enzyme Inhibitors / pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphocytes, Tumor-Infiltrating / immunology ; Lymphocytes, Tumor-Infiltrating / metabolism ; Macrophages / immunology ; Macrophages / metabolism ; Male ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, Nude ; Mice, SCID ; Neoplasm Metastasis ; Neoplastic Stem Cells / immunology ; Neoplastic Stem Cells / metabolism* ; Neoplastic Stem Cells / pathology ; PC-3 Cells ; Polycomb Repressive Complex 1 / antagonists & inhibitors ; Polycomb Repressive Complex 1 / genetics ; Polycomb Repressive Complex 1 / metabolism* ; Prostatic Neoplasms / drug therapy ; Prostatic Neoplasms / immunology ; Prostatic Neoplasms / metabolism* ; Prostatic Neoplasms / pathology ; Receptors, Androgen / deficiency ; Receptors, Androgen / genetics ; Receptors, CCR4 / genetics ; Receptors, CCR4 / metabolism ; Signal Transduction ; T-Lymphocytes, Regulatory / immunology ; T-Lymphocytes, Regulatory / metabolism ; Tumor Escape* / drug effects ; Xenograft Model Antitumor Assays

Keywords: MDSCs ; Tregs ; angiogenesis ; combination therapy ; epigenetics ; immune evasion ; immune microenvironment ; metastasis ; preclinical compound ; stemness

Abstract: The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC.