Abstract TMEM-028: OMENTAL MACROPHAGES REGULATE OVARIAN CANCER METASTATIC COLONIZATION
Authors: Venkatesh Krishnan, Bruce Schaar, Carrie Rinker-Schaeffer, Oliver Dorigo
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: Metastatic ovarian cancer remains an urgent clinical problem. The homing and invasion of cancer cells into the omental adipose tissue, which is the preferred site of ovarian cancer metastasis, is a critical step in disease progression. Improving patient outcomes requires a mechanistic understanding of how cancer cells colonize the omentum and ultimately give rise to widespread peritoneal metastases. Unlike other peritoneal adipose tissues, omental adipose contains immune aggregates known as milky spots, which contain macrophages, B, T, natural killer (NK), and stromal cells within capillary nests. Our data shows that milky spots play an active role in ovarian cancer metastatic colonization to the omentum. We hypothesize that macrophages within the milky spots play a crucial role in promoting ovarian cancer progression. METHODS AND RESULTS: Immunocompetent mice were injected with syngeneic murine ID8 and immunocompromised mice were injected with human (SKOV3ip.1, CaOV3, HeyA8), ovarian cancer cells. After seven days post-injection, mice were sacrificed and analyzed for the distribution of cancer cells. We found metastases in omental milky spots and not in adipose lacking milky spots. Use of genetic models (C57BL/6, Athymic Nude, Beige Nude, Rag1-/-, Igh6-/- mice) ruled out a requirement for B, T, and NK cells in ovarian cancer cell homing to milky spots, suggesting a critical role for macrophages in this process. Our recent data shows that depletion of omental adipose tissue macrophages abrogates cancer cell colonization of milky spots. Furthermore, factors secreted by omental macrophages have an enhanced ability to promote ovarian cancer migration in vitro, compared to factors secreted by other peritoneal adipose tissue macrophages. Screening omental adipose conditioned medium with a cytokine array revealed higher concentration of macrophage-secreted cytokines (e.g., MCSF-1, IL10) than control medium conditioned by adipose lacking milky spots. Examination of naïve human omentum confirmed the presence of macrophages in immune clusters. Clinical samples from patients with high-grade serous cancer showed the incidence of microscopic metastases within omental immune clusters. Importantly, RNA-Seq of CD45+CD11b+F4/80+ flow-sorted macrophages from omentum and mesentery of naïve and cancer-bearing mice revealed that omental macrophages have a very distinct gene expression signature. CONCLUSION: We demonstrate that omental milky spots are the preferential sites for cancer colonization of peritoneal adipose. Further, we have identified omental macrophages as the key mediators of colonization. Future studies are focused on understanding the cancer cell-macrophage interactions that can be targeted therapeutically to disrupt metastatic growth and extend disease-free survival. Citation Format: Venkatesh Krishnan, Bruce Schaar, Carrie Rinker-Schaeffer, Oliver Dorigo. OMENTAL MACROPHAGES REGULATE OVARIAN CANCER METASTATIC COLONIZATION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-028.