Intravesical BCG induces CD4+ T Cell Expansion in a Clinically Relevant Immune Competent Model of Bladder Cancer

Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity.膀胱内卡介苗（BCG）免疫疗法是治疗非肌层浸润性膀胱癌的标准治疗方案，但其作用机制仍不甚明确。现有研究提示，固有免疫与适应性免疫应答均与BCG的抗肿瘤活性相关。既往研究已间接证实T细胞的重要性，并观察到BCG治疗后膀胱组织内CD4阳性T细胞（CD4+ T cells）数量升高，但T细胞亚群的特征尚未被完全阐明。本研究在免疫健全、具有临床相关性的膀胱癌啮齿类动物模型中，探究了效应T细胞与调节性T细胞之间的关联。研究数据显示，在N-甲基亚硝基脲（MNU）诱导的膀胱癌大鼠模型中，肿瘤进展伴随CD8/FoxP3比值下降，这与适应性免疫功能减弱相一致。与之相反，膀胱内BCG治疗可导致尿路上皮内CD4阳性T细胞群体出现显著且短暂的升高，且其疗效与免疫原性均优于膀胱内化疗方案。值得注意的是，对治疗后膀胱内CD4阳性T细胞与CD8阳性T细胞（CD8+ T cells）进行全转录组表达谱分析发现，BCG治疗后二者的基因表达差异微乎其微。综上，本研究结果表明，尽管BCG可诱导T细胞募集至膀胱组织，但T细胞的表型并未发生显著改变，这提示将T细胞活化剂与BCG联合使用或可提升其临床抗肿瘤活性。