Abstract 799: Obesity-associated modulation of the immune microenvironment of the omental fat band during peritoneal seeding of ovarian cancer

Abstract

Abstract Ovarian cancer is the leading cause of death by gynecological malignancy in the Western world, the fourth most deadly cancer in women. Typically originating from the layer of epithelial cells surrounding the ovary, cancer cells exfoliate to disseminate throughout the peritoneal cavity. The omental fat band (OFB) has been described as a secondary lymphoid organ composed of heavily vascularized fatty tissue interspersed with immune cell aggregates, or “milky spots”. It is also the site of preferential tumor cell adhesion and invasion within the peritoneal cavity, and is removed at the time of surgical debulking in ovarian cancer patients as a preventative measure. Several studies have suggested that obesity is a risk factor for ovarian cancer, but it is unclear whether the obese state directly influences peritoneal dissemination of ovarian cancer. Here, we set out to elucidate the obesity-related changes in the immune microenvironment of the OFB in the homeostatic state as well as following cancer cell adhesion and outgrowth. Our lab has developed a spontaneously transformed murine ovarian surface epithelial (MOSE) cell model that mimics the progressive stages of ovarian cancer following long-term passaging. Importantly, these cells can be used to study the immune microenvironment of tumor cells in an immunocompetent host. EGFP-expressing MOSE-L (late) cells that had been selected in vivo for an aggressive phenotype were injected i.p. into 6 month-old C57Bl/6 mice and changes to the OFB immune microenvironment were evaluated after 6, 24 hrs and 4 weeks. Furthermore, mice fed a high- or low-fat diet (40 or 5% calories as fat, respectively) were used to determine the effects of diet-induced obesity on cancer cell seeding and outgrowth. Immunofluorescence microscopy, real-time PCR and flow cytometry were used to determine tumor cell attachment and growth and identify changes in OFB immune cell populations. Early seeding (24 hrs post-injection) of EGFP-MOSE-L cells at the OFB was increased in high-fat fed mice. Preliminary data from mRNA expression profiling identified genes in the OFB that were i) obesity-associated, ii) a direct response to tumor cell seeding or iii) were exacerbated in the obese microenvironment following tumor cell seeding. This suggests that obesity-associated signaling events could be polarizing the OFB towards a pro-tumorigenic microenvironment. There were also distinct differences in the immune cell populations within the OFB as function of both obesity and time post-tumor cell seeding. These results indicate that ovarian cancer cells preferentially populate the OFB early during peritoneal dissemination and are capable of escaping immune surveillance mechanisms. This study sheds light on the obesity-induced changes in immunomodulatory events associated with tumor seeding and outgrowth in the peritoneal cavity. Supported by NIH CA118846 to EMS and PCR Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 799. doi:10.1158/1538-7445.AM2011-799