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Regulation of CD8+ T cells infiltration and immunotherapy by circMGA/HNRNPL complex in bladder cancer

Oncogene volume 42, pages 1247–1262 (2023)Cite this article

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Abstract

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.

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Fig. 1: Identification and distribution of circMGA.
Fig. 2: CircMGA increases the accumulation of CCL5.
Fig. 3: CircMGA interacts with HNRNPL protein in bladder cancer.
Fig. 4: HNRNPL enhances the stability of circMGA and CCL5.
Fig. 5: CircMGA promotes the stability of CCL5 mRNA through HNRNPL.
Fig. 6: CircMGA/HNRNPL complex mediates recruitment of CD8+ T cells.
Fig. 7: Biological implications of circMGA in bladder cancer.
Fig. 8: Schematic model for the mechanisms of circMGA/HNRNPL complex in hindering bladder cancer progression.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The mRNA expression profile data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database with the number of GSE182310 (token: qjmluawubtupvur).

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Acknowledgements

We would like to thank the Department of Urology of the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China), the patients, and their families for donating bladder cancer tissues and paired adjacent normal tissues. We would also like to thank Yunxue Li for correcting spelling and grammatical errors in our manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81974396, 81773282, 82072840, 82102734 and 81902593), the Natural Science Foundation of Hubei province (2022CFB165) and Wuhan Science and Technology Plan Application Foundation Frontier Project (2020020601012247).

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  1. These authors contributed equally: Jiayin Sun, Hui Zhang, Wenjie Wei.

Authors and Affiliations

  1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Jiayin Sun, Hui Zhang, Wenjie Wei, Xingyuan Xiao, Chao Huang, Liang Wang, He Zhong, Yangkai Jiang, Guosong Jiang & Xiaoping Zhang

  2. Department of Urology, Wuhan No.1 Hospital, Wuhan, 430022, China

    Fuxin Zheng

  3. Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China

    Hongmei Yang

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Contributions

X Zhang, G Jiang and H Yang were the overall study principal investigators who conceived and designed the study. J Sun, H Zhang, and W Wei performed experiments, analyzed data, and drafted the manuscript. X Xiao, C Huang, and L Wang were responsible for recruitment of bladder cancer subjects and collection of clinical information and biological specimens. H Zhong, Y Jiang, F Zheng analyzed bioinformatics data. All authors read and approved the final manuscript.

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Correspondence to Hongmei Yang, Guosong Jiang or Xiaoping Zhang.

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Sun, J., Zhang, H., Wei, W. et al. Regulation of CD8+ T cells infiltration and immunotherapy by circMGA/HNRNPL complex in bladder cancer. Oncogene 42, 1247–1262 (2023). https://doi.org/10.1038/s41388-023-02637-2

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