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

Author:

Yu Guoyu1ORCID,Corn Paul G.2,Mak Celia Sze Ling2,Liang Xin2,Zhang Miao3,Troncoso Patricia3ORCID,Song Jian H.2ORCID,Lin Song-Chang1ORCID,Song Xingzhi4,Liu Jingjing4,Zhang Jianhua4,Logothetis Christopher J.2,Melancon Marites P.56,Panaretakis Theocharis2,Wang Guocan26,Lin Sue-Hwa126

Affiliation:

1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

5. Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

6. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030

Abstract

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.

Funder

HHS | NIH | National Cancer Institute

DOD | USA | MEDCOM | CDMRP | DOD Prostate Cancer Research Program

Cancer Prevention and Research Institute of Texas

Publisher

Proceedings of the National Academy of Sciences

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