Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy

Abstract

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 tumorspecific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. 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. We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. 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 and that these cells had the highest levels of the exhaustion marker PD-1. 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.

The impact of biological sex on diseases of the urinary tract

“…In the case of bladder cancer, AR antagonism may have a different outcome. We applied the BBN model to transgenic URO-Ova mice expressing a model antigen from the urothelium to follow tumor-specific T cell responses during immunotherapy 148 . We found that tumorspecific T cells infiltrated the bladder more robustly in male tumor-bearing mice treated with BCG and PD-L1 immunotherapies compared to female tumor-bearing mice, which may be one reason why men have better bladder cancer outcomes than women 148 .…”

“…We applied the BBN model to transgenic URO-Ova mice expressing a model antigen from the urothelium to follow tumor-specific T cell responses during immunotherapy 148 . We found that tumorspecific T cells infiltrated the bladder more robustly in male tumor-bearing mice treated with BCG and PD-L1 immunotherapies compared to female tumor-bearing mice, which may be one reason why men have better bladder cancer outcomes than women 148 . Importantly, however, whether this difference is mediated by sex hormones, sex chromosomes, or another mechanism is unclear and would require preclinical studies modulating each of these factors before one could conclude that AR antagonism is a viable treatment approach.…”