Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers.

骨髓来源的抑制细胞（MDSC）是促成免疫逃逸的关键因素之一。本研究的目的是调查MDSCs是否可以成为治疗顺铂耐药膀胱癌的新靶标。我们建立了顺铂耐药膀胱癌细胞系（MB49R，MBT-2R和T24R），并评估了趋化因子的表达和MDSC的扩增。我们还通过使用MB49R异种移植模型消耗有或没有α-PD-L1抗体的MDSC来评估抗肿瘤作用。与其亲本菌株相比，顺铂耐药细胞中CXCL1，CXCL2和CCL2的趋化因子表达增加。与MB49R肿瘤中的多形核MDSC（PMN-MDSC）相比，单核MDSC（Mo-MDSC）的观察频率更高。在体内，使用α-Gr1和α-Ly6C抗体靶向PMN-和Mo-MDSC的联合疗法可显着减少肿瘤体积，并增加肿瘤中CD8 T细胞的浸润。最后，共同靶向泛MDSCs和PD-L1显着降低了肿瘤的生长。这些发现表明，靶向MDSCs可能增强免疫检查点抑制剂在顺铂耐药性膀胱癌中的治疗效果。