Influence of sex on immunosurveillance and metastatic tropism in novel mouse models of clear cell renal cell carcinoma 4060

Abstract Description Sex bias in renal cell carcinoma (RCC) is marked by males having twice the incidence and mortality of females, along with larger, higher-grade tumors and greater metastatic burden. Using two syngeneic RCC mouse models, one immune checkpoint blockade (ICB)-resistant (Vhl, Trp53, Rb1 mutations) & one ICB-responsive (Vhl, Bap1, Cdkn2a/b mutations), we evaluated these sex-specific differences. Tumor cells were implanted in male & female immune-deficient (ID, NOD-SCID IL2Rγnull) & immune-competent (IC, albino B6) mice, with tumor progression monitored via ultrasound and metastases assessed postmortem. IC females developed smaller tumors with lower penetrance compared to males, while ID mice showed no sex differences, indicating a protective role of the female immune system. Flow cytometry revealed females had more circulating T-cells. Interestingly in tumors, CD8+ T-cells in the ICB-resistant model correlated with larger tumors (males), while in the ICB-responsive model, they correlated with smaller tumors (females), suggesting CD8+ T-cells can have pro-tumor/anti-tumor effects depending on the microenvironment. Metastases occurred only in ID mice, with males showing more liver metastases and females more lung metastases. This pattern persisted in IC mice using a metastatic derivative line, suggesting hormonal or non-adaptive immunity influences metastatic seeding. These findings underscore sex-related immunologic differences in immune surveillance and metastatic tropism in RCC. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)