Abstract C183: Inhibition of CSF1 receptor signaling targets tumor associated macrophages in a murine ovarian cancer model.

Abstract

Abstract Rationale: CSF1 receptor (CSF1R) mediated signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs). TAMs support tumor growth by several mechanisms including suppressing anti-tumor immune responses via the M2 macrophage subpopulation. Macrophages are found in the ascites and tumor tissue of patients with ovarian cancer and therefore present a suitable target for therapy. This study evaluates the effect of pharmacologic CSF1R inhibition on the profile of intraperitoneal macrophages in a murine model of ovarian cancer. In addition, we assessed the direct effect of CSF1R inhibition on several established human ovarian cancer cell lines. Methods: To establish an orthotopic ovarian cancer model, we injected murine ID8 epithelial ovarian cancer cells into the ovarian bursa of immuno-competent C57BL6 mice. ID8 cells were labeled with the luciferase gene for bioluminescence. Upon establishment of tumor disease and ascites, mice were treated with daily oral doses of the selective CSF-1R inhibitor GW2580. Ascites and tumor tissue was assessed for the presence of CD11b+Gr-1loLy6Chi mononuclear myeloid-derived suppressor cells (MDSCs) and CD11b+F4/80+ tumor-associated macrophages (TAMs). The human ovarian cancer cell lines OVCAR5, IGROV1 and SKOV3 were treated with CSF1R inhibitors and cell proliferation assessed. Results: In vivo gene imaging showed ID8 tumor growth initially confined to the ovary with subsequent metastatic spread to the peritoneal cavity closely mimicking the growth pattern of human ovarian cancer. In animals with established metastatic tumor disease and ascites, GW2580 treatment caused a significant reduction in the ascites volume to about 25% of the level in untreated animals. GW2580 induced a drastic reduction in TAMs and MDSCs in ascites and intraperitoneal tumor tissue. Both MHCII+ and MHCII- TAM subpopulations were reduced equally. OVCAR5, IGROV1 and SKOV3 showed a decrease in cell proliferation when treated with CSF1R inhibitors albeit at higher doses (>10 M). Conclusion: Inhibition of CSF1R signaling in vivo reduces immune-suppressive TAMs and MDSCs in an intraperitoneal murine ovarian cancer model. In addition, CSF1 decreases ovarian cancer cell proliferation. This suggests that CSF1R inhibition might have dual therapeutic effects by modulating the intraperitoneal microenvironment and directly targeting ovarian cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C183.