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

Autor:	Yu G; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Corn PG; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Mak CSL; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Liang X; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Zhang M; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Troncoso P; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Song JH; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Lin SC; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Song X; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Liu J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Zhang J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Logothetis CJ; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Melancon MP; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030., Panaretakis T; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030., Wang G; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030., Lin SH; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Aug 13; Vol. 121 (33), pp. e2402903121. Date of Electronic Publication: 2024 Aug 05.
DOI:	10.1073/pnas.2402903121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu