Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Department of Urology, Queen's University, Kingston, Ontario, Canada.
Int J Cancer. 2024 Jul 15;155(2):352-364. doi: 10.1002/ijc.34897. Epub 2024 Mar 14.
Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.
高危非肌肉浸润性膀胱癌（NMIBC）的治疗包括膀胱内免疫治疗卡介苗（BCG）；然而，疾病复发和进展经常发生。全身免疫对于成功的癌症免疫治疗至关重要；因此，NMIBC 的复发可能是由于局部免疫治疗后抗肿瘤免疫的全身激活不足。我们之前报道过，循环单核细胞中获得的系统适应性免疫（一种先天免疫记忆形式）与接受 BCG 治疗的 NMIBC 患者的复发时间延长有关。在此，我们使用 NMIBC 小鼠模型比较了膀胱内和静脉内（全身）BCG 免疫治疗对局部和外周免疫微环境的影响。我们还评估了 BCG 诱导的适应性免疫是否调节抗肿瘤免疫反应。与导致肿瘤促进免疫微环境的膀胱内 BCG 相比，静脉内 BCG 导致具有增加的细胞毒性 T 淋巴细胞（CTL）比例和减少的髓系来源抑制细胞（MDSC）比例的抗肿瘤膀胱微环境。与膀胱内 BCG 相比，静脉内 BCG 治疗后引流淋巴结、脾脏和骨髓中发生了向抗肿瘤免疫的极化。与静脉内 BCG 预处理相比，膀胱内 BCG 预处理与肿瘤生长速度加快有关。适应性免疫与肿瘤免疫微环境的重塑有关，因为用 BCG 训练的巨噬细胞与表达卵清蛋白的膀胱肿瘤细胞共注入增加了肿瘤特异性 CTL 的比例。此外，BCG 训练的树突状细胞表现出增强的抗原摄取和呈递，并促进 CTL 增殖。我们的数据支持这样一种观点，即全身免疫激活促进了抗肿瘤反应，并且 BCG 诱导的适应性免疫在驱动抗肿瘤适应性免疫中很重要。
