Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8602, Japan.
Genes (Basel). 2023 Mar 9;14(3):678. doi: 10.3390/genes14030678.
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.
免疫检查点抑制剂（ICI）治疗策略改变了癌症治疗的模式。然而，这种治疗方法仅对一部分患者有效。人们认为，对 ICI 的反应差异取决于癌症类型及其肿瘤微环境（TME）。TME 有利于癌症的进展和转移，还可以帮助癌细胞逃避免疫攻击。为了提高对 ICI 的反应，了解 TME 如何维持的机制至关重要。蛋白精氨酸甲基转移酶 5（PRMT5）在其底物上二甲基化精氨酸残基，在基因表达的表观遗传调控、信号转导和 mRNA 剪接保真度中具有重要作用。通过这些功能，PRMT5 可以支持癌细胞的免疫逃逸。PRMT5 是调节性 T 细胞（Treg）功能所必需的，促进了癌症干细胞和上皮-间充质转化。TME 中的特定因素可以帮助招募 Tregs、肿瘤相关巨噬细胞和髓系来源的抑制细胞进入肿瘤。此外，PRMT5 抑制抗原呈递以及干扰素和趋化因子的产生，而这些是招募 T 细胞进入肿瘤所必需的。总的来说，PRMT5 支持免疫抑制性 TME。因此，抑制 PRMT5 有助于恢复免疫周期，并使免疫系统介导的癌细胞消除成为可能。
