Identification of Sex Differences in Tumor-Specific T Cell Infiltration in Bladder Tumor-Bearing Mice Treated with BCG Immunotherapy

Abstract : BACKGROUND: Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumor-specific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. OBJECTIVE: To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. CONCLUSIONS: We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men. METHOD: We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. RESULTS: We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations. Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8+ T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy whereas regulatory T cells had higher levels of the exhaustion marker PD-1 in female mice.