PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression

Jiang, Yongshuai; Yuan, Yuanyang; Chen, Ming; Li, Shengzhe; Bai, Jun; Zhang, Yuanteng; Sun, Ying; Wang, Guojue; Xu, Haiyan; Wang, Ziyu; Zheng, Yingxia; Nie, Hong

doi:10.7150/thno.59605

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Nanotheranostics 2024; 8(3): 380-400. [Abstract] [Full text] [PDF]

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International Journal of Medical Sciences

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Theranostics 2021; 11(18):9162-9176. doi:10.7150/thno.59605 This issue Cite

Research Paper

PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression

Yongshuai Jiang^1#, Yuanyang Yuan^1#✉, Ming Chen², Shengzhe Li¹, Jun Bai¹, Yuanteng Zhang¹, Ying Sun¹, Guojue Wang¹, Haiyan Xu¹, Ziyu Wang¹, Yingxia Zheng^3✉, Hong Nie^1✉

1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2. Department of Gynecology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
3. Department of Laboratory Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
^#These authors contribute equally to this article.

Citation:

Jiang Y, Yuan Y, Chen M, Li S, Bai J, Zhang Y, Sun Y, Wang G, Xu H, Wang Z, Zheng Y, Nie H. PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics 2021; 11(18):9162-9176. doi:10.7150/thno.59605. https://www.thno.org/v11p9162.htm

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Abstract

Rationale: Protein arginine methyltransferase 5 (PRMT5) is an oncogene that promotes tumor cell proliferation, invasion and metastasis. However, the underlying mechanisms by which PRMT5 contributes to the progression of cervical cancer and especially the tumor microenvironment remain poorly understood.

Methods: PRMT5 expression level was analyzed by Q-PCR, western blot, immunohistochemistry, and TCGA database. The role of PRMT5 in tumor growth was observed by transplanted tumor models, and the function of T cells in tumor microenvironment and in vitro co-culture system was investigated through flow cytometry. The transcriptional regulation of PRMT5 was analyzed using luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The therapeutic effect of PRMT5 inhibitor was evaluated in a cervical cancer cell line transplanted tumor model.

Results: We observed that the mRNA and protein expression levels of PRMT5 were increased in cervical cancer tissues, and the high expression of PRMT5 was associated with poor outcomes in cervical cancer patients. The absence of PRMT5 significantly inhibited tumor growth in a cervical cancer transplanted tumor model, and importantly, PRMT5 absence in tumors led to increase the number and enhance the function of tumor infiltrating T cells. Mechanistically, PRMT5 enhanced the transcription of STAT1 through symmetric dimethylation of histone H3R2 and thus promoted PD-L1 expression in cervical cancer cells. Moreover, in an in vitro co-culture system, knockdown of PRMT5 in tumor cells could directly enhance the expression of IFN-γ, TNF-α and granzyme B in T cells. These results suggested that PRMT5 promoted the development of cervical cancer by the crosstalk between tumor cells and T cells. Furthermore, the PRMT5 inhibitor EPZ015666 treatment could suppress tumor growth in a cervical cancer transplanted tumor model.

Conclusion: Our results clarify a new mechanism which PRMT5 knockdown in cervical cancer cells drives an antitumor function via reprogramming T cell-mediated response and regulating PD-L1 expression. Thus, our study highlights that PRMT5 may be a potential target for cervical cancer therapy.

Keywords: PRMT5, PD-L1, STAT1, cervical cancer, tumor microenvironment

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APA

Jiang, Y., Yuan, Y., Chen, M., Li, S., Bai, J., Zhang, Y., Sun, Y., Wang, G., Xu, H., Wang, Z., Zheng, Y., Nie, H. (2021). PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics, 11(18), 9162-9176. https://doi.org/10.7150/thno.59605.

ACS

Jiang, Y.; Yuan, Y.; Chen, M.; Li, S.; Bai, J.; Zhang, Y.; Sun, Y.; Wang, G.; Xu, H.; Wang, Z.; Zheng, Y.; Nie, H. PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics 2021, 11 (18), 9162-9176. DOI: 10.7150/thno.59605.

NLM

CSE

Jiang Y, Yuan Y, Chen M, Li S, Bai J, Zhang Y, Sun Y, Wang G, Xu H, Wang Z, Zheng Y, Nie H. 2021. PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression. Theranostics. 11(18):9162-9176.

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