Abstract B008: Unraveling the sexually dimorphic immune microenvironment in gastric cancer

Abstract Gastric cancer is a sexually dimorphic disease. Male patients have twice the incidence, are diagnosed at a younger age, and have worse survival outcomes than females. Whether there are molecular mechanisms that underlie these sex-based differences is unclear. We generated genetically engineered mice on C57BL/6 backgrounds with parietal cell-specific conditional deletions of Trp53 and Cdh1, two tumor suppressors commonly lost in gastric cancer (Atp4b-Cre; Trp53 flox/flox ; Cdh1 flox/flox , “APC” mice). APC mice developed gastric cancer with 100% penetrance and median overall survival was significantly longer in females (50.6 weeks, N = 20) than males (41.7 weeks, N = 23; p < 0.001). At the time of death, serum were collected and circulating cytokines were quantified using multiplex ELISA. Females had significantly higher levels of circulating IFN-γ (60.8 pg/mL vs. 10.9 pg/mL; p = 0.02) and CCL4 (257 pg/mL vs. 118.3 pg/mL; p = 0.001), suggesting enhanced cytotoxic lymphocyte and macrophage activity. Bulk RNA sequencing of tumors revealed significant enrichment of Hallmark Gene Sets associated with type I and II interferon responses and antigen presentation pathways in females. These findings suggested an immune-mediated basis for the survival difference seen between male and female APC mice. To further explore the immune microenvironment, we derived cell lines from APC tumors and performed flank injections into C57BL/6 mice. Tumor volumes at 6 weeks were not significantly different between sexes (645 mm2 in females vs. 951 mm2 in males; p = 0.35). However, flow cytometry revealed marked immune differences in total CD8+ T cells (2.4% in females vs. 0.63% in males vs.; p = 0.05), activated CD8+ T cells (23.0% vs. 9.2%; p < 0.001), dendritic cells (2.6% vs. 1.3% of myeloid cells; p = 0.05), and a trend toward increased M1 macrophages in females (1.6% vs. 0.9%; p = 0.06). We next evaluated the role of sex hormones in mediating sex-associated differences in gastric cancer. Females underwent oophorectomies (F-O) or sham operations (F-S), while males underwent orchiectomies (M-O) or sham operations (M-S). Median overall survival was significantly longer in F-S mice (47.1 weeks, N = 7) compared to F-O mice (44.1 weeks, N = 6; p=0.003). In contrast, median overall survival did not differ in M-S (44.3 weeks, N = 7) than M-O (44.7 weeks, N = 4; p=0.8). In conclusion, we demonstrate sex-based differences in survival in an autochthonous genetically engineered mouse model of gastric cancer, consistent with clinical observations that female human patients have improved overall survival than female patients. Our findings implicate the immune system as potential mediators of these differences. Preliminary data suggests hormone deprivation impacts overall survival of female mice, but not male mice. Future work is directed at identifying the molecular mechanism between female sex, sex hormones, and improved overall survival. Citation Format: Ryan T. Heslin, Shu Xiao, Morgan F. Pettigrew, Nafeesah Fatimah, Hsien-Tsung Lai, Suntrea T.G. Hammer, Sam C. Wang. Unraveling the sexually dimorphic immune microenvironment in gastric cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B008.