放疗联合髓系来源抑制细胞靶向治疗克服免疫冷型膀胱癌治疗抵抗。
Irradiation plus myeloid-derived suppressor cell-targeted therapy for overcoming treatment resistance in immunologically cold urothelial carcinoma.
机构信息
Department of Urology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.
Department of Urology, Ishikiri Seiki Hospital, Yayoicho, Higashi Osaka City, Osaka, 579-8026, Japan.
出版信息
Br J Cancer. 2023 Jun;128(12):2197-2205. doi: 10.1038/s41416-023-02244-8. Epub 2023 Apr 17.
BACKGROUND
Radiotherapy (RT) has recently been highlighted as a partner of immune checkpoint inhibitors. The advantages of RT include activation of lymphocytes while it potentially recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). This study aimed to investigate the mechanism of overcoming treatment resistance in immunologically cold tumours by combining RT and MDSC-targeted therapy.
METHODS
The abscopal effects of irradiation were evaluated using MB49 and cisplatin-resistant MB49R mouse bladder cancer cells, with a focus on the frequency of immune cells and programmed cell death-ligand 1 (PD-L1) expression in a xenograft model.
RESULTS
MB49R was immunologically cold compared to parental MB49 as indicated by the fewer CD8 T cells and lower PD-L1 expression. Polymorphonuclear MDSCs increased in both MB49 and MB49R abscopal tumours, whereas the infiltration of CD8 T cells increased only in MB49 but not in MB49R tumours. Interestingly, PD-L1 expression was not elevated in abscopal tumours. Finally, blocking MDSC in combination with RT remarkably reduced the growth of both MB49 and MB49R abscopal tumours regardless of the changes in the frequency of infiltrating CD8 T cells.
CONCLUSIONS
The combination of RT and MDSC-targeted therapy could overcome treatment resistance in immunologically cold tumours.
背景
放射治疗（RT）最近被强调为免疫检查点抑制剂的合作伙伴。RT 的优点包括激活淋巴细胞，同时可能招募免疫抑制细胞，如髓系来源的抑制细胞（MDSCs）。本研究旨在探讨通过联合 RT 和 MDSC 靶向治疗克服免疫冷肿瘤治疗抵抗的机制。
方法
使用 MB49 和顺铂耐药的 MB49R 小鼠膀胱癌细胞评估照射的远隔效应，重点关注异种移植模型中免疫细胞和程序性死亡配体 1（PD-L1）表达的频率。
结果
MB49R 与亲本 MB49 相比免疫冷，表现为 CD8 T 细胞较少和 PD-L1 表达较低。多形核 MDSCs 在 MB49 和 MB49R 远隔肿瘤中均增加，而 CD8 T 细胞的浸润仅在 MB49 中增加，而在 MB49R 肿瘤中则没有。有趣的是，远隔肿瘤中 PD-L1 表达没有升高。最后，阻断 MDSC 联合 RT 可显著减少 MB49 和 MB49R 远隔肿瘤的生长，而与浸润 CD8 T 细胞频率的变化无关。
结论
RT 和 MDSC 靶向治疗的联合可能克服免疫冷肿瘤的治疗抵抗。
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