Regulation of CD8+ T cells infiltration and immunotherapy by circMGA/HNRNPL complex in bladder cancer
Regulation of CD8+ T cells infiltration and immunotherapy by circMGA/HNRNPL complex in bladder cancer
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circMGA/HNRNPL 复合物对膀胱癌 CD8 T 细胞浸润和免疫治疗的调节
DOI：
10.1038/s41388-023-02637-2
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发表时间：
2023-03-03
期刊：
影响因子：
8
通讯作者：
Zhang, Xiaoping
中科院分区：
文献类型：
--
作者：
Sun, Jiayin;Zhang, Hui;Zhang, Xiaoping
靶向免疫检查点抑制剂的免疫疗法的有限成功在很大程度上归因于缺乏浸润性CD 8（+）T淋巴细胞。Circular RNA（circRNA）是一种新型的非编码RNA，与膀胱癌的发生、发展密切相关，但其在膀胱癌CD 8（+）T细胞浸润和免疫治疗中的作用尚不清楚。在本文中，我们发现circMGA是一种肿瘤抑制性circRNA，可触发CD 8（+）T细胞的化学吸引并增强免疫治疗功效。在机制上，circMGA通过与HNRNPL相互作用来稳定CCL 5 mRNA。反过来，HNRNPL增加了circMGA的稳定性，形成了一个反馈回路，增强了circMGA/HNRNPL复合物的功能。有趣的是，circMGA和抗PD-1之间的治疗协同作用可以显著抑制异种移植膀胱癌生长。综上所述，结果表明，circMGA/HNRNPL复合物可能是癌症免疫治疗的靶向，并且该研究推进了我们对circRNA在抗肿瘤免疫中的生理作用的理解。
The limited success of immunotherapies targeting immune checkpoint inhibitors is largely ascribed to the lack of infiltrating CD8(+) T lymphocytes. Circular RNAs (circRNAs) are a novel type of prevalent noncoding RNA that have been implicated in tumorigenesis and progression, while their roles in modulating CD8(+) T cells infiltration and immunotherapy in bladder cancer have not yet been investigated. Herein, we uncover circMGA as a tumor-suppressing circRNA triggering CD8(+) T cells chemoattraction and boosting the immunotherapy efficacy. Mechanistically, circMGA functions to stabilize CCL5 mRNA by interacting with HNRNPL. In turn, HNRNPL increases the stability of circMGA, forming a feedback loop that enhances the function of circMGA/HNRNPL complex. Intriguingly, therapeutic synergy between circMGA and anti-PD-1 could significantly suppress xenograft bladder cancer growth. Taken together, the results demonstrate that circMGA/HNRNPL complex may be targetable for cancer immunotherapy and the study advances our understanding of the physiological roles of circRNAs in antitumor immunity.