In vivo hemin conditioning targets the vascular and immunological compartments and restrains prostate tumor development

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study we assessed how hemin, a pharmacological inducer of Heme Oxygenase-1 (HO-1), impacts upon prostate cancer (PCa) development in an in vivo conditioning model. <p>Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used PCa patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes.</p> <p>Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histological analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated HUVEC exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1 conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neo-vascularization in an in vivo Matrigel plug assay. Additionally, hemin boosted CD8⁺ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo. A significant systemic increase in CD8⁺ T-cell frequency was observed in pre-conditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of PCa patient-derived xenografts and PCa patient samples with mild HO-1 and low Gal-1 expression levels.</p> Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response.

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