SENP3调控树突状细胞抗肿瘤功能的机制研究

Dendritic cells (DCs) can recognize, process and present tumor antigens, resulting CD8+ T cells activation to specifically kill tumor cells, which is crucial in tumor immunity. Fully understand the regulation mechanism of DCs activity in tumor immunity is significant for realizing the pathogenesis of tumors and cancer treatment. SUMOylation is an important proteins posttranslational modification pathway, which is involved in tumorigenesis, while the molecular mechanism is obscure. Our preliminary results indicated that SENP3 mediated DCs in response to tumor DNA to activate the interferon-stimulated gene (STING) signaling pathway, which regulated the activity and anti-tumor function of DCs. In view of the important role of DCs in tumor immunity, we will further study the specific molecular mechanism of SENP3 regulating STING signaling pathway and DCs activity. We hypothesize that SENP3 plays an important role in DCs anti-tumor immunity. We will find the target of SENP3 in DCs. Moreover, we will clarify how SENP3 regulates specific molecular target SUMOylation modification to regulate STING signaling pathway. Furthermore, we will explore the role of SENP3-STING axis in DCs anti-tumor immunity. It is expected that the research results will not only provide a theoretical basis for understanding the role of SUMOylation modification in tumor immunity, but also provide new molecular targets and ideas for tumor therapy.

树突状细胞（DCs）可以识别、加工和递呈肿瘤抗原，激活T细胞特异性杀伤肿瘤细胞，在肿瘤免疫中至关重要，充分认识肿瘤免疫中DCs活性的调控机制，对于理解肿瘤发病进程和肿瘤治疗意义重大。类泛素化修饰（SUMOylation）是一种重要的蛋白翻译后修饰途径，参与肿瘤发生发展，然而其对肿瘤免疫应答的调控作用尚不清楚。申请人初步实验结果表明：SENP3介导DCs响应肿瘤DNA，激活干扰素刺激基因（STING）信号通路，调节DCs活性，调控DCs抗肿瘤功能。鉴于此，推测SENP3在DCs抗肿瘤免疫中发挥重要作用，本项目拟开展以下研究：1、鉴定SENP3在DCs中的分子靶点；2、阐明SENP3如何调节特定分子靶点类泛素化修饰调控STING信号通路；3、探究DCs中SENP3-STING轴在肿瘤免疫中的作用。预期研究成果将为认识类泛素化修饰在肿瘤免疫中的作用提供理论基础，为肿瘤治疗提供新的分子靶点和思路。

树突状细胞可以识别、加工、递呈肿瘤抗原，在免疫治疗中十分关键，阐明树突状细胞在肿瘤微环境中的调控机制对于抗肿瘤免疫和抗肿瘤药物开发极为重要。项目负责人前期研究表明：SENP3介导DCs响应肿瘤DNA，进而激活STING信号通路，调节DCs活性，调控DCs抗肿瘤功能。基于此，我们推测SENP3可以调控DCs抗肿瘤功能。我们采用RNA-seq、肿瘤模型、分子生化等技术手段阐明：SENP3可以响应肿瘤微环境ROS，促进其蛋白稳定，调节底物蛋白IFI204去类泛素化修饰，促进STING信号通路的活化，增强STING依赖的DCs抗肿瘤功能。临床结直肠癌样本实验显示：DCs中的SENP3感知ROS并介导IFI16的去类泛素化修饰，促进STING信号激活。本项研究阐述了氧化应激在肿瘤微环境中促进STING激活的作用机制，提示肿瘤治疗联合抗氧化剂可能会降低临床疗效，而 SENP3作为氧化应激感应蛋白可能为肿瘤免疫治疗提供一个潜在的治疗靶点。本项目研究成果将为抗肿瘤药物的开发和临床转化提供坚实的理论基础。相关研究成果已发表于Molecular cell。. 项目负责人在本项目的完成中得到了严谨系统的科学训练，并获得中国博士后第13批特别资助（站中），博士后出站在南京医科大学任教授一职。在本项目执行期间，培养研究生两名。