Abstract 1659: Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells

Abstract Ovarian cancer exhibits the lowest long-term survival rates amongst all gynecological cancers, warranting more research directed at finding novel therapies, especially for late-stage disease. Inflammation is known to affect cancer progression, with tumor-promoting or repressive effects possible in different contexts, where the types of leukocytes at the tumor site are heavily implicated in disease prognosis. Tumor-associated macrophages and T-regulatory cells, for example, are known to promote tumor growth by inhibiting the anti-cancer response and by secreting pro-angiogenic factors. Importantly, the specific processes and cellular signaling pathways leading up to leukocyte infiltration in different cancer types remain to be fully elucidated. We hypothesize that dsRNA in the vicinity of ovarian cancer cells (such as from a viral infection or cellular debris) can activate pro-inflammatory regulators in tumor cells, in particular the NF-KB transcription factor, the aberrant over-activation of which is implicated in many cancers. NF-KB activation results in increased production and secretion of numerous cytokines that can in turn recruit pro-angiogenic leukocytes to the tumor microenvironment, thus favoring cancer progression. Herewith, we evaluated the production of numerous cytokines after dsRNA treatment in mouse and human ovarian cancer cells. Additionally, we determined which of the four known dsRNA receptors contributes most to this process. Consistently with our hypothesis, we have shown an increase in several pro-inflammatory cytokines (eg. CCL5 and IL6) in response to dsRNA treatment in both human and mouse ovarian cancer cell lines. We have also determined that the dsRNA receptor MDA5 contributes the most to dsRNA-induced cytokine secretion in both human and mouse ovarian cancer cell lines employing siRNA-directed knock-down of each receptor. Altogether, these data suggest that dsRNA-induced signaling in ovarian cancer cells may facilitate a tumor-favoring environment; thus dsRNA-sensing receptors may constitute attractive therapeutic targets for cancer immunotherapy. Further studies in our lab will determine the specific signaling pathways responsible for the upregulated cytokines as well as use a mouse model to examine the effect of dsRNA receptor knock-down in the cancer cells on tumor growth, angiogenesis, and the leukocyte infiltration profile. Citation Format: Maria Muccioli, Michelle Pate, Fabian Benencia. Characterizing cytokine secretion in response to dsRNA treatment in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1659. doi:10.1158/1538-7445.AM2014-1659