The Role of PRMT5 in Immuno-Oncology

Abstract

Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The TME is favorable for cancer progression and metastasis and can also help cancer cells to evade immune attacks. To improve the response to ICIs, it is crucial to understand the mechanism of how the TME is maintained. Protein arginine methyltransferase 5 (PRMT5) di-methylates arginine residues in its substrates and has essential roles in the epigenetic regulation of gene expression, signal transduction, and the fidelity of mRNA splicing. Through these functions, PRMT5 can support cancer cell immune evasion. PRMT5 is necessary for regulatory T cell (Treg) functions and promotes cancer stemness and the epithelial-mesenchymal transition. Specific factors in the TME can help recruit Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells into tumors. In addition, PRMT5 suppresses antigen presentation and the production of interferon and chemokines, which are necessary to recruit T cells into tumors. Overall, PRMT5 supports an immunosuppressive TME. Therefore, PRMT5 inhibition would help recover the immune cycle and enable the immune system-mediated elimination of cancer cells.

Keywords: PRMT5; immune checkpoint; immune evasion; immuno-oncology; tumor microenvironment.

Figure 1

Seven steps of the cancer-immunity cycle. APC, antigen-presenting cell (e.g., dendritic cell). This figure was illustrated using Adobe Illustrator 2022 (Adobe, San Jose, CA, USA) based on ref. [3].

Figure 2

Cancer immunoediting. NKT cells, natural killer T cells; NK cells, natural killer cells; DC, dendritic cells. This figure was illustrated using Adobe Illustrator 2022 based on ref. [4].

Figure 3

Protein arginine methyltransferase (PRMT)-mediated arginine methylation. All PRMT family proteins modify monomethylated arginine. Next, type I PRMTs modify asymmetrical methylated arginine and type II PRMTs modify symmetrically methylated arginine, while type III PRMT (PRMT7) modifies only monomethyl arginine. This figure was illustrated using Adobe Illustrator 2022 and was modified from our previous work [31].

Figure 4

The roles of protein arginine methyltransferase 5 (PRMT5). (a,b): Schematic illustrations of PRMT5-mediated epigenetic regulation of gene expression. (c,d): The PRMT5-meditated mRNA splicing machinery. (e): PRMT5-mediated signal transduction and transcriptional regulatory molecules. Each figure is the author’s original image, illustrated using Adobe Illustrator 2022.

Figure 5

The roles of protein arginine methyltransferase 5 (PRMT5) in immune evasion. PRMT5 attenuates type I interferon (IFN) and chemokine production and represses antigen presentation, suppressing cancer cell recognition by T cells and infiltration of T cells into the tumor ①. PRMT5 activates forkhead box P3 (FOXP3), which is essential for regulatory T cell (Treg) maintenance ②. PRMT5 maintains cancer stemness and cancer cell proliferation ③. PRMT5 upregulates epithelial-to-mesenchymal transition (EMT)-associated gene expression, leading to metastasis ④. CSCs and EMT promote regulatory T cell (Treg), tumor-associated macrophage (TAM), and myeloid-derived suppressor cell (MDSC) recruitment into the tumor microenvironment (TME), supporting immune evasion. This figure is the author’s original image, illustrated using Adobe Illustrator 2022.