Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization

• 成果类型: Article
• 署名作者: Yu, Guoyu; Corn, Paul G.; Mak, Celia Sze Ling; Liang, Xin; Zhang, Miao; Troncoso, Patricia; Song, Jian H.; Lin, Song - Chang; Song, Xingzhi; Liu, Jingjing; Zhang, Jianhua; Logothetis, Christopher J.; Melancon, Marites P.; Panaretakis, Theocharis; Wang, Guocan; Lin, Sue - Hwa
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8593
• DOI: 10.1073/pnas.2402903121
• 发表日期: 2024-08-13
• 关键词: metastasis; radium-223; expression; survival; cxcl14

摘要

Immune checkpoint therapy has limited efficacy for patients with bone- metastatic castration- resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC- induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32- gene M2- like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206- positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor- induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2- like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor- associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl- TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC- to- osteoblast (EC- to-OSB) transition, the precursors of tumor- induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2- like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC- to-OSB transition reduced the levels of M2- like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC- to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC.