Abstract IA23: Targeting the inflammatory cytokine network of serous ovarian cancer

Abstract

Abstract Our work involves characterization of the tumor microenvironment of high-grade serous ovarian cancer, HGSC, especially peritoneal metastases, and investigation of novel therapies that target interactions between malignant and non-transformed cells. In mouse models and human biopsies, we have found prominent populations of CD4+ and CD8+ T cells, and CD68+ macrophages within and surrounding the malignant cell areas of peritoneal tumors. Fibroblasts surround this tumor microenvironment and clusters of B cells are also close by the malignant cells in tertiary lymphoid structures. Twenty-50% of the tumor mass of these peritoneal metastases is comprised of non-transformed cells. In mouse models we find that malignant cells adhere rapidly to peritoneal surfaces and within 48 hours these cells attract peritoneal leukocytes. In tumor deposits that form in avascular areas, the cell mass becomes vascularized within 2-6 weeks depending on the model. Three key cytokine/chemokine mediators of cancer-related inflammation, TNF, CXCL12 and IL6, are involved in an autocrine cytokine network in malignant cells from ovarian cancer. This network has paracrine actions on angiogenesis, infiltration of myeloid cells and NOTCH signalling in both murine xenografts and human HGSC biopsies. With a cohort of matched omental biopsies and blood samples taken from HGSC patients at diagnosis, and after 3-4 cycles of chemotherapy, we are now able to obtain information on the influence of chemotherapy on cancer-related inflammation. Neutralising antibodies or siRNA to individual members of this TNF network reduce angiogenesis, myeloid cell infiltration and experimental peritoneal tumor growth. The dependency of network genes on TNF was demonstrated by their down regulation in tumor cells from patients with advanced ovarian cancer following the infusion of anti-TNF antibodies. We also investigated the therapeutic potential of an anti-human IL6 antibody (siltuximab). The clinical, pre-clinical and in silico experiments showed that antibodies to IL-6 can have multiple actions within the tumor microenvironment of ovarian cancer including reductions in cytokine production, tumor angiogenesis and tumor macrophage infiltrate as well as reducing the paraneoplastic thrombocytosis found in some patients with HGSC. We are now investigating rational combinations of anti-cytokine antibodies with other treatments that target the tumor microenvironment. In particular we are investigating signaling pathways that are upregulated when ovarian cancer cells are treated with neutralizing anti-IL-6 antibodies. Our experiments are leading us to suggest ways to combine inflammatory cytokine antagonists with other treatments for serous ovarian cancer. Citation Format: Frances Rosemary Balkwill. Targeting the inflammatory cytokine network of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA23.