Prostate cancer-induced endothelial-to-osteoblast transition generates an immunosuppressive bone tumor microenvironment

Abstract

Immune checkpoint therapy has limited efficacy for patients with bone metastatic castrate-resistant prostate cancer (bmCRPC). In this study, we revealed a novel mechanism that may account for the relative resistance of bmCRPC to immune checkpoint therapy. We found that prostate cancer (PCa)-induced bone via endothelial-to-osteoblast (EC-to-OSB) transition causes an ingress of M2-like macrophages, leading to an immunosuppressive bone tumor microenvironment (bone-TME). Analysis of a bmCRPC RNA-seq dataset revealed shorter overall survival in patients with an M2-high versus M2-low signature. Immunohistochemical (IHC) analysis showed CD206+M2-like macrophages were enriched in bmCRPC specimens compared with primary tumors or lymph node metastasis. In osteogenic PCa xenografts, CD206+macrophages were enriched adjacent to tumor-induced bone. FACS analysis showed an increase in CD206+cells in osteogenic tumors compared to non-osteogenic tumors. Genetic or pharmacological inhibition of the EC-to-OSB transition reduced aberrant bone and M2-like macrophages in osteogenic tumors. RNAseq analysis of tumor-associated macrophages from osteogenic (bone-TAMs) versus non-osteogenic (ctrl-TAMs) tumors showed high expression of an M2-like gene signature, canonical and non-canonical Wnt pathways, and a decrease in an M1-like gene signature. Isolated bone-TAMs suppressed T-cell proliferation while ctrl-TAMs did not. Mechanistically, EC-OSB hybrid cells produced paracrine factors, including Wnts, CXCL14 and LOX, which induced M2 polarization and recruited M2-like TAMs to bone-TME. Our study thus links the unique EC-to-OSB transition as an “upstream” event that drives “downstream” immunosuppression in the bone-TME. These studies suggest that therapeutic strategies that inhibit PCa-induced EC-to-OSB transition may reverse immunosuppression to promote immunotherapeutic outcomes in bmCRPC.SignificanceThe insight that prostate cancer-induced bone generates an immunosuppressive bone tumor microenvironment offers a strategy to improve responses to immunotherapy approaches in patients with bone metastatic castrate-resistant prostate cancer.

Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone

“… 70 Numbers of CD206+ M2 macrophages are increased in castrate resistant disease 70 , 87 , 88 , 89 and consistent with our findings for ST6GAL1, a recent study showed CD206+ M2 macrophages are upregulated in bone metastatic CRPC specimens compared with primary tumours or lymph node metastases. 90 M2 like macrophages can secrete pro-metastatic factors and cytokines to suppress immune responses initiated by T cell leading to immunological silence 91 and strategies to target prostate tumour TAMs are being investigated as approaches to re-sensitise the prostate TME to immunotherapy. 66 , 92 Previous studies have implicated tumour-derived sialic acids with the differentiation of monocytes to macrophages with a pathogenic phenotype.…”