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. 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. 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.

中文翻译：

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BCG免疫疗法治疗膀胱肿瘤小鼠的肿瘤特异性T细胞浸润的性别差异的鉴定

背景：膀胱癌是男性第四大最常见的癌症。但是，妇女通常被诊断出患有晚期疾病，并且预后较差。目前尚不清楚基于免疫的性别差异是否会导致这种差异。另外，缺乏用于在肿瘤发展或对治疗的反应的背景下研究膀胱癌中的肿瘤特异性免疫的模型。目的：为了解决这一具体的未满足需求，我们将常用的模型抗原卵清蛋白整合入两个公认的膀胱癌模型中；原位MB49细胞系模型和致癌性BBN膀胱癌模型。方法：我们测试了这些模型的实用性，以研究在男女双方进行免疫治疗的情况下的肿瘤特异性免疫。结果：我们发现BCG疫苗接种了，在多次BCG滴注的情况下，每周一次BCG滴注之前不会给荷瘤小鼠带来免疫特异性的好处。此外，在雄性小鼠睾丸中发展的肿瘤，不包括使用MB49模型直接研究基于性别的免疫差异。在BBN模型中，我们观察到，在BCG免疫治疗的情况下，与雌性膀胱相比，浸润在雄性膀胱中的肿瘤抗原特异性CD8 + T细胞更多，而调节性T细胞在雌性小鼠中具有更高的耗尽标记物PD-1。结论：我们提出改进的BBN模型将有助于我们了解膀胱癌中肿瘤特异性免疫的产生方式。此外，BBN膀胱癌模型可能有助于揭示肿瘤特异性免疫力的性别差异，