The prognostic implications of macrophage polarization in advanced and therapy-resistant prostate cancer

Abstract

Abstract Tumor-associated macrophages (TAMs) are components of the spatial microenvironment of many solid neoplasms. In prostate cancer (PCa), TAMs are linked to a poor prognosis. PCa is characterized by enhanced tumor lipid production and TAM lipid accumulation. However, the interplay between lipid-producing tumor cells and TAM lipid uptake has yet to be determined. Human prostate tumor tissue microarrays were evaluated for TAM (CD68+) and M2/M1 (CD206+/CD86+) levels correlated with tumor aggressiveness by multiplex immunohistochemistry. Standard PCa cells 22rv1, PC3 and DU145 were used to develop chemoresistant sublines which were validated using dose-response viability assays and immunoblotting for resistance-associated markers and lipid-producing enzymes. Cancer cell-derived extracellular vesicles (EVs) were isolated from cell culture supernatants by size exclusion chromatography and were incubated with U937-derived macrophages, followed by flow cytometric evaluation of M1 and M2 markers. Proteomic evaluation of human prostate tumors indicates that CD68+ TAMs correlate with aggressive, metastatic PCa. Furthermore, a higher M2-to-M1 ratio also correlates with metastatic disease compared to normal or localized tumors. Chemoresistant PCa cells exhibited an enhanced lipogenic phenotype compared to naive cells and the over-production of lipids was linked to EV-mediated reprogramming of macrophages toward an M2-like phenotype. These findings indicate that alternative activation of macrophages is linked to aggressive, therapy resistant PCa. Moreover, our data suggest that tumor lipid metabolism may influence tumor-associated macrophage phenotype and function through EV-mediated intercellular signaling. Puerto Rico Science Research and Technology Trust