Abstract 975: Obesity-induced changes in the tumor microenvironment impact the response to chemotherapy and overall ovarian cancer metastatic success

Abstract Background The majority of women with epithelial ovarian cancer (OvCa) are diagnosed with metastatic disease, resulting in a poor 5-year survival of 31%. Obesity is a recognized epidemic that increases OvCa incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity (DIO) mouse model where a significantly enhanced tumor burden was associated with a decreased M1/M2 tumor-associated macrophage (TAM) ratio (Liu Y et al. Can, Res. 2015; 75:5046-57). TAMs are the most abundant immune cell type in the ovarian tumor microenvironment and are generally categorized as M1-polarized (cytotoxic to tumor cells), or M2-polarized (growth promoting). For this study we sought to examine if a similar correlation between body mass index (BMI) and TAMs were also true for human ovarian cancer patients. Furthermore, we used the DIO mouse model to examine any potential effect of obesity on response to chemotherapy. Methods We analyzed high grade serous ovarian tumors from 6 normal weight patients (BMI 20-25), and 10 obese patients (BMI ≥35) for an in-depth analysis of immune cells using MultiOmyx™, an immunofluorescence (IF) multiplexing assay. After multiplexing FFPE sections with a custom panel of 13 immuno-oncology biomarkers, images were analyzed by applying the deep-learning based cell classification platform NeoLYTX.For the analysis of response to chemotherapy we used a DIO mouse model in which mice were fed a low-fat diet (LFD) vs high-fat diet (HFD) and then injected with ID8-Trp53-/- cells to establish tumor burden. Mice bearing equivalent tumor burden were treated with weight-adjusted standard of care chemotherapy. After sacrifice, remaining tumor burden was evaluated by quantitative fluorescence imaging. Results We found that the mean M1/M2 ratio in obese OvCa patients was nearly half (ratio=0.16) compared to patients who were normal weight (ratio=0.29), consistent with our previously published mouse data. Quantitation of residual tumor burden in the mouse model showed significantly reduced efficacy of chemotherapy (i.e., greater remaining tumor burden) in HFD mice (n=11/cohort). The M1/M2 TAM ratio in these mouse tumors is now under evaluation. Conclusions Our observations suggest that the negative impact of obesity on OvCa survival may be due in part to an increased M1/M2 TAM ratio and reduced response to chemotherapy. These data will be key to a more detailed understanding of the contribution of host obesity to ovarian tumor progression. Citation Format: Anna Juncker-Jensen, Yueying Liu, Tyvette S. Hilliard, Nicholas Stavrou, M Sharon Stack. Obesity-induced changes in the tumor microenvironment impact the response to chemotherapy and overall ovarian cancer metastatic success [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 975.