Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Unit 1906, PO Box 301429, Houston, TX 77054/77030-1429, USA; Department of Urology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Cancer Cell. 2019 Aug 12;36(2):139-155.e10. doi: 10.1016/j.ccell.2019.06.009. Epub 2019 Jul 18.
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.
转移部位的免疫逃逸机制尚未完全阐明。我们发现多梳抑制复合物 1（PRC1）驱动双阴性前列腺癌（DNPC）在骨骼和内脏器官中的定植。体内遗传筛选鉴定出 CCL2 是 PRC1 诱导的最具转移潜能的基因。CCL2 调控自我更新，并诱导 M2 样肿瘤相关巨噬细胞和调节性 T 细胞的募集，从而将转移起始与免疫抑制和新生血管生成协调起来。PRC1 的催化抑制剂与免疫检查点治疗合作，逆转这些过程，并抑制 DNPC 的基因工程小鼠移植模型中的转移。这些结果表明 PRC1 协调干性与免疫逃逸和新生血管生成，并指出针对 DNPC 中的 PRC1 的潜在临床应用。
