Abstract A48: M2 macrophage inhibition reverses vascular leaks that cause malignant ascites in late-stage epithelial ovarian cancer

Abstract

Abstract Introduction: Malignant ascites is a common symptom of epithelial ovarian cancer (EOC) that greatly reduces the quality of life for patients and has no good treatment options that target the source of the problem. Our study aims to find the cause of ascites in order for us to better know how to safely reverse this pathology. Experimental Procedures: Murine ID8 EOC tumor cells were implanted intraperitoneally or orthotopically into female C57BL/6 mice, and bioluminescent imaging was used to track the progress of the cancer. GW2580, a very selective colony stimulating factor 1 receptor (CSF1R) inhibitor, was given to mice for two weeks once ascites appeared. Flow cytometry, histology, and endothelial cell permeability assays were used to analyze the effects of blocking macrophages in the model. Flow cytometry and endothelial cell permeability assays were also used to analyze and characterize EOC patient ascites samples. Results: CSF1R inhibition blocked specifically M2 macrophages from the ascites and dramatically reduced ascites volume, leaving mice less anemic. When M2 macrophages numbers were reduced in the ascites, CD8 T cell numbers increased, causing the ascites microenvironment to be less immunosuppressive. Peritoneal vasculature that had grown disorganized and leaky became normalized with treatment. Ascites sera from GW2580-treated mice protected against endothelium permeability, while control mouse sera caused the endothelium to become leaky. This data agrees with our finding that patient ascites sera cause more endothelium permeability if more macrophages were present in the ascites. We also saw macrophage and myeloid cell depletion in the tumor and systemically with GW2580 treatment, along with a consistent reduction in tumor burden. Conclusions: M2 macrophages are key players that cause ascites through deregulating peritoneal vasculature. The leaky vessels are normalized once these macrophages are physically and functionally blocked from the ascites microenvironment. This finding suggests that macrophage inhibition could be a powerful tool for ascites management. VEGF inhibitors are currently in clinical trials for malignant ascites treatment with mixed, sometimes deadly, results. Targeting macrophages, the source of many vessel-deregulating proteins, might make it more difficult for resistance to build up than when just one protein, such as VEGF, is blocked, and CSF1R inhibitors have been shown to be safe and well-tolerated in the clinic. This novel approach toward ascites and EOC management should be further studied. Future work will focus on finding the specific factors that caused the vessel deregulation and normalization, looking at functional differences between macrophage from control and GW2580-treated ascites, seeing if endothelial cell-macrophage direct interaction may have any effects on the vasculature, and performing this study in genetic and human models of EOC. Citation Format: Diana Moughon, Huanhuan He, Shiruyeh Schokrpur, Ziyue Jiang, Madeeha Yaqoob, John David, Luisa Iruela-Arispe, Oliver Dorigo, Lily Wu. M2 macrophage inhibition reverses vascular leaks that cause malignant ascites in late-stage epithelial ovarian cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A48. doi:10.1158/1538-7445.CHTME14-A48