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.

中文翻译：

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膀胱癌的全身与局部卡介苗免疫疗法可促进抗肿瘤微环境：训练有素的免疫力的新作用

高风险非肌层浸润性膀胱癌 (NMIBC) 的治疗涉及卡介苗 (BCG) 膀胱内免疫治疗；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​​肿瘤免疫系统激活不理想所致。我们之前报道过，循环单核细胞中系统获得的训练有素的免疫力（一种先天免疫记忆的形式）与接受卡介苗治疗的 NMIBC 患者的复发时间延长有关。在此，我们使用 NMIBC 小鼠模型来比较膀胱内与静脉内（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 诱导的训练免疫是否调节抗肿瘤免疫反应。与膀胱内注射卡介苗（产生促进肿瘤的免疫微环境）相比，静脉注射卡介苗产生抗肿瘤膀胱微环境，其特征是细胞毒性T淋巴细胞（CTL）比例增加，而髓源性抑制细胞比例减少。静脉内与膀胱内 BCG 治疗后，引流淋巴结、脾脏和骨髓中出现抗肿瘤免疫的极化。与静脉内 BCG 预处理相比，膀胱内 BCG 预处理与肿瘤生长率增加相关。经过训练的免疫有助于重塑肿瘤免疫微环境，因为将经过 BCG 训练的巨噬细胞与表达卵白蛋白的膀胱肿瘤细胞共同滴注增加了肿瘤特异性 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的概念：全身免疫激活促进抗肿瘤反应，并且卡介苗诱导的训练免疫对于驱动抗肿瘤适应性免疫很重要。