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

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.

PRMT5 is a therapeutic target in choroidal neovascularization

“…The Matrigel tube formation assay is a widely used, reproducible model system to study either the activation or inhibition of angiogenic pathways in vitro. Knockdown of PRMT5 in various cancer cells can suppress the protumorigenic functions of PRMT5 (Wei et al, 2012; Chiang et al, 2017; Deng et al, 2017; Jiang et al, 2021). Therefore, we sought to assess whether genetic or chemical inhibition of PRMT5 affects tube formation in HRECs and iCEC2 cells.…”

Stearoyl-CoA desaturase 1 regulates malignant progression of cervical cancer cells

“…The binding between KLF9 and SCD1 was determined using a ChIP assay (Beyotime. Nantong, China) [ 29 ]. The cells were cross-linked with methanol and terminated with glycine, followed by lysis and sonication.…”

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review

“…PRMT5 blockade resulted in increased expression of PD-L1 with subsequent increase in CD4+ and CD8+ T cell activity as characterized by IFN-γ, TNF-α, and granzyme B. [ 58 ] GSK3326595 was studied in a mouse melanoma (B16 and YUMM1.7 cell tumor allograft) model alone and in combination with anti-PD1 therapy. Combination therapy showed significant decrease in tumor size as compared with PRMT5 inhibitor or anti-PD-1 therapies alone and, similarly, significant increase in survival.…”