The role of macrophage production of transforming growth factor-ß in epithelial ovarian cancer progression.

Abstract

e17100 Background: Increased Transforming Growth Factor- ß (TGF-ß) signaling is associated with poorer prognosis in advanced stage epithelial ovarian carcinoma (EOC). Macrophages are known to produce high amounts of TGF-ß which plays a significant role in immune suppression in the tumor microenvironment Methods: A syngeneic mouse model was created using ID8 cell lines with p53 knocked out. These cells were injected intraperitoneally to establish tumor challenge. One mouse model was treated with TGF-ß monoclonal antibody at the time of tumor inoculation. A second model utilized a mouse line that was engineered to eliminate production of TGF-ß from macrophages specifically. Tumors were harvested and weighed after 42 days of tumor challenge. Flow cytometry was used to analyze differences in CD8 T-cell and T regulatory cell populations. Results: Tumor weights were significantly reduced in mice treated with anti-TGF-ß monoclonal antibody (p = 0.02). Average tumor weights were 125mg vs 101mg comparing non-treated to treated mice. Also, ascites volume was measured using syringe aspiration from peritoneal cavity at the time of sacrifice. Mean ascites volume was 4.7mL vs 2.9 mL (p = 0.004) in untreated mice versus mice treated with monoclonal antibody. In mice with macrophages specific deletion of TGF-ß production, tumors were unable to be established in these mice and omental weights were comparable to tumor naive mice with a mean weight of 34mg compared to 115 mg in wild type mice. In both mouse models there was a significant difference in CD8 : Tregs ratio in omental tumor microenvironment. Conclusions: Increased amounts of TGF-ß contribute to increased tumor invasion and migration, while loss of TGF-ß results in both a decrease in tumor burden and a decrease in suppressors of T cell activity. Inhibition of TGF-ß, demonstrated with a monoclonal antibody can effectively reduce TGF-β signaling. The macrophages within the omental tumor microenvironment are a source of large amounts of TGF-ß and when lost result in an inability to establish tumors in intraperitoneal tumors.