Prostate Cancer-Induced Endothelial-Cell-to-Osteoblast Transition Drives Immunosuppression in the Bone-Tumor Microenvironment Through Wnt Pathway-Induced M2 Macrophage Polarization

Authors

Guoyu Yu
Paul G Corn
Celia Sze Ling Mak
Xin Liang
Miao Zhang
Patricia Troncoso
Jian H Song
Song-Chang Lin
Xingzhi Song
Jingjing Liu
Jianhua Zhang
Christopher J Logothetis
Marites P Melancon
Theocharis Panaretakis
Guocan Wang
Sue-Hwa Lin

Publication Date

8-13-2024

Journal

Proceedings of the National Academy of Sciences of the United States of America

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.

Keywords

Male, Tumor Microenvironment, Humans, Bone Neoplasms, Animals, Wnt Signaling Pathway, Mice, Macrophages, Endothelial Cells, Osteoblasts, Prostatic Neoplasms, Castration-Resistant, Cell Line, Tumor, Prostatic Neoplasms, Tumor-Associated Macrophages

Comments

Supplementary Materials

Data Availability Statement

PMID: 39102549