Abstract A65: Toll-like receptor 3 signaling in ovarian cancer.

Abstract

Abstract The purpose of this study is to examine the cytokine secretion (in vitro) and leukocyte infiltration profiles (in vivo) in response to Toll-Like Receptor 3 (TLR3) activation in murine epithelial ovarian carcinoma. Ovarian cancer is the most deadly gynecological neoplasm, typically treated with surgery and chemotherapy, and has a less than a 50% 5-year survival rate. Drug resistance develops frequently, and it is necessary to investigate more targeted therapies. Chronic inflammation, which is seen in many cancers, can render an immunosuppressive tumor microenvironment characterized by cytokines that promote leukocyte infiltration, which can potentiate angiogenesis, and subsequent tumor growth and metastasis. Pathways that can generate such inflammation are important to characterize as they may be targeted in the development of novel cancer therapeutics. One regulator of inflammation in some types of epithelial ovarian cancer is TLR3, a protein that senses dsRNA and activates NF-κB, a potent initiator of cytokine secretion. Although typically expressed in immune cells, TLR3 is also present in cancer cells, and may function to direct inflammation at the tumor site towards an immunosuppressive state capable of recruiting pro-angiogenic leukocytes. Using PCR, ELISA, western blot, and microarray experiments on siRNA-generated TLR3-knock-downs and control samples, we are characterizing the cytokine secretion profiles following TLR3 activation with synthetic dsRNA ligands. Furthermore, we will employ this ovarian cancer cell line (ID8) with C57BL/6 mice to generate transplantation tumors and determine the effects of TLR3 signaling on the leukocyte population and presence of angiogenic molecules at the tumor site using flow cytometry and immunohistochemistry. We have determined that treatment of ID8 epithelial ovarian carcinoma cells with TLR3 ligands poly (I:C) or poly (A:U) results in increased secretion of pleiotropic cytokines, such as CCL5 and IL6, that may potentiate leukocyte migration to the tumor site. In vivo studies with C57BL/6 mice will determine whether this TLR3-induced cytokine secretion in the tumor cells translates to the physiological environment and promotes leukocyte infiltration and angiogenesis. By elucidating the contribution of TLR3 to the recruitment of pro-angiogenic leukocytes in ovarian epithelial carcinoma, the results of this project may be useful in the development of anti-angiogenic therapies for certain ovarian tumors. Citation Format: Maria Muccioli, Michelle Pate, Fabian Benencia. Toll-like receptor 3 signaling in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A65.