去泛素化酶USP21调控结肠癌浸润Treg细胞功能的机理研究

Treg cells are known to restrict anti-tumor immune responses and promote tumor survival. Therefore, release from the suppressive influence of Treg cells or conversion of these cells into Th1-like inflammatory cells might provide beneficial traits in the tumor microenvironment to support anti-tumor responses. A recent study has characterized a population of FOXP3lo Th1-like Treg cells in colorectal cancer, which produced higher amounts of IFN-γ after in vitro stimulation and also predicted better prognosis. We recently found that the E3 deubiquitinase USP21 prevents FOXP3 degradation through deubiquitination and therefore restricts the generation of Th1-like Treg cells. Meanwhile, USP21-deficient Treg cells display impaired immune suppressive activities and produce more IFN-γ, which could potentially break tumor immune tolerance. Based on these previous findings, we will further analyze the role of USP21 in tumor-infiltrated Treg cells and explore the anti-tumor effects of USP21 inhibitors in colorectal cancer.

调节性T（Treg）细胞抑制抗肿瘤免疫反应，从而促进肿瘤生长。因此，抑制Treg细胞的免疫抑制功能或者将其转化成Th1-like Treg细胞均有助于增强抗肿瘤免疫反应。在部分结肠癌患者的肿瘤组织中，研究人员最近鉴定出一群低表达关键转录因子FOXP3蛋白的Th1-like Treg细胞，它们分泌更多的炎性细胞因子IFN-γ，并预示结肠癌病人存在更好的生存率。我们的前期实验结果显示去泛素化酶USP21通过去泛素化修饰阻止FOXP3蛋白降解，并抑制Th1-like Treg细胞的产生。同时，USP21缺陷的Treg细胞免疫抑制功能减弱，分泌更多的炎性细胞因子IFN-γ，可能会有助于打破肿瘤免疫耐受。基于我们的前期数据，本项目申请将进一步分析去泛素化酶USP21对结肠癌浸润Treg细胞功能的调控机制，并考察USP21抑制剂干预和治疗结肠癌的可行性，从而为结肠癌的治疗提供新线索。