Wang Bo, He Zhihua, Yu Hao, Ou Ziwei, Chen Junyu, Yang Meihua, Fan Xinxiang, Lin Tianxin, Huang Jian
Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, 510120, People's Republic of China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Cancer Immunol Immunother. 2022 Jun;71(6):1507-1517. doi: 10.1007/s00262-021-03063-7. Epub 2021 Oct 31.
Bacillus Calmette-Guerin (BCG) immunotherapy can prevent recurrence and progression in selected patients with non-muscle-invasive bladder cancer (NMIBC); however, significant adverse events and treatment failure suggest the need for alternative agents. A commercial anti-infection vaccine comprises a genetically engineered heat-killed Pseudomonas aeruginosa (PA) expressing many mannose-sensitive hemagglutination (MSHA) fimbriae, termed PA-MSHA, which could be a candidate for bladder cancer intravesical therapy. In an immunocompetent orthotopic MB49 bladder cancer model, we characterized the antitumor effects and mechanisms of PA-MSHA compared with those of BCG. Three weekly intravesical PA-MSHA or BCG treatments reduced tumor involvement; however, only PA-MSHA prolonged survival against MB49 implantation significantly. In non-tumor-bearing mice after treatment, flow-cytometry analysis showed PA-MSHA and BCG induced an increased CD4/CD8 ratio, the levels of effector memory T cell phenotypes (CD44, CXCR-3, and IFN-γ), and the proportion of CD11bLy6GLy6CIA/IE mature macrophages, but a decrease in the proportion of CD11bLy6GLy6CIA/IE monocytic myeloid-derived suppressor cells (Mo-MDSCs) and the expression of suppressive molecules on immune cells (PD-L1, PD-1, TIM-3, and LAG-3). Notably, PA-MSHA, but not BCG, significantly reduced PD-1 and TIM-3 expression on CD4 T cells, which might account for the better effects of PA-MSHA than BCG. However, in tumor-bearing mice after treatment, the increased proportion of Mo-MDSCs and high expression of PD-L1 might be involved in treatment failure. Thus, modulating the balance among adaptive and innate immune responses was identified as a key process underlying PA-MSHA-mediated treatment efficacy. The results demonstrated mechanisms underlying intravesical PA-MSHA therapy, pointing at its potential as an alternative effective treatment for NMIBC.
卡介苗（BCG）免疫疗法可预防部分非肌层浸润性膀胱癌（NMIBC）患者的复发和进展；然而，严重的不良事件和治疗失败表明需要替代药物。一种商用抗感染疫苗包含一种基因工程热灭活铜绿假单胞菌（PA），其表达多种甘露糖敏感血凝素（MSHA）菌毛，称为PA-MSHA，它可能是膀胱癌膀胱内治疗的候选药物。在具有免疫活性的原位MB49膀胱癌模型中，我们比较了PA-MSHA与BCG的抗肿瘤作用及其机制。每周进行三次膀胱内PA-MSHA或BCG治疗可减少肿瘤累及；然而，只有PA-MSHA能显著延长抵抗MB49植入的生存期。在治疗后的无瘤小鼠中，流式细胞术分析显示PA-MSHA和BCG诱导CD4/CD8比值增加、效应记忆T细胞表型（CD44、CXCR-3和IFN-γ）水平升高、CD11bLy6GLy6CIA/IE成熟巨噬细胞比例增加，但CD11bLy6GLy6CIA/IE单核髓系来源抑制细胞（Mo-MDSCs）比例降低以及免疫细胞上抑制分子（PD-L1、PD-1、TIM-3和LAG-3）的表达降低。值得注意的是，PA-MSHA而非BCG能显著降低CD4 T细胞上PD-1和TIM-3的表达，这可能解释了PA-MSHA比BCG效果更好的原因。然而，在治疗后的荷瘤小鼠中，Mo-MDSCs比例增加和PD-L1高表达可能与治疗失败有关。因此，调节适应性免疫和先天性免疫反应之间的平衡被确定为PA-MSHA介导的治疗效果的关键过程。结果揭示了膀胱内PA-MSHA治疗的机制，表明其作为NMIBC替代有效治疗方法的潜力。
