共刺激分子4IgB7H3介导T细胞耗竭在胶质瘤侵袭和迁移中的作用及机制研究

Glioma is the most common primary brain tumor, with poor conventional treatment effect and being easy to relapse, thus. We must explore new ideas to treat this kind of tumor, including immune therapy. Previous research suggested that: 1) costimulatory molecule 4IgB7H3 induce the immune escape in glioma, of which Hh signaling is involved in the regulation; 2) Hh signals may be involved in T cell exhaustion induced by TGF-β, and the specific mechanism is not clear. Accordingly, we put forward a hypothesis: Controlled of tumor microenvironment, such as Hh signal, TGF-β, 4IgB7H3 induce T cell exhaustion and promote the invasion and migration of glioma cells. After establish glioma cell and animal model, we will use RNAi, nucleic acid/protein detection, apoptosis/cycle test, cytotoxic test, invasion and migration experiments to investigate the mechanism of T cell exhaustion in invasiveness and migration of glioma cells; focus on the mechanism that 4IgB7H3 may be guided by Hh signal and TGF-β; combined with the clinical and follow-up data, observe the relationship between 4IgB7H3 expression and tumor markers, factors of progress and recurrence of glioma; dissect the role and the mechanism of 4IgB7H3 in glioma immune pathological changes. The aim of this research is to provide a theoretical basis to understand mechanism of glioma immune escape mediated by signaling pathway, and put forward new ideas and intervention targets for tumor immune treatment.

胶质瘤是最常见的原发神经肿瘤，常规治疗效果差，易复发，需探索包括免疫治疗在内的治疗新思路。前期研究提示：1）共刺激分子4IgB7H3诱导胶质瘤免疫逃逸，Hh信号参与调控；2）Hh信号可能参与TGF-β诱导的T细胞耗竭，具体机制不清，据此提出假设：4IgB7H3通过Hh信号、TGF-β等肿瘤微环境调控，诱导T细胞耗竭，促进胶质瘤细胞侵袭与迁移。拟建立胶质瘤细胞和动物模型，运用RNAi、核酸/蛋白检测、细胞凋亡/周期、细胞毒检测、侵袭和迁移实验等方法，探讨胶质瘤细胞侵袭与迁移中，诱导T细胞耗竭的机制；重点阐述Hh信号、TGF-β等肿瘤微环境对4IgB7H3的介导机制；结合临床和随访资料，观察4IgB7H3表达与肿瘤分子标记、进展复发等因素的相关性，探讨分析4IgB7H3在胶质瘤免疫病理改变中的机制和作用；为理解信号通路介导胶质瘤免疫逃逸提供理论依据，为肿瘤免疫治疗提出新思路和干预靶点。

本研究进一步研究4IgB7H3在胶质瘤免疫逃逸中的基因功能，分析胶质瘤4IgB7H3的表达状态与T细胞无能的关系，评价Hh信号、TGF-β等肿瘤微环境可能发挥的作用大小，4IgB7H3在胶质瘤细胞中的异常高表达诱导T细胞无能，促进胶质瘤细胞的侵袭及迁移等恶性生物学特征，并在鼠胶质瘤模型上加以证实，探讨其基因功能的分子机制。在手术切除的胶质瘤标本中研究4IgB7H3表达与胶质瘤分子病理分型、转移及复发等恶性生物学特征的关系，进一步揭示4IgB7H3与胶质瘤预后的关系。在胶质瘤细胞株及实验鼠胶质瘤模型上证实敲减4IgB7H3能改善T细胞无能，并抑制胶质瘤细胞的增殖、侵袭及转移等恶性生物学特征，观察其潜在的治疗作用和可能的毒副作用。通过探讨分析4IgB7H3在胶质瘤免疫病理改变中的机制和作用，为理解信号通路介导胶质瘤免疫逃逸提供理论依据，为肿瘤免疫治疗提出新思路和干预靶点。同时通过胶质瘤多组学分析和临床诊断应用相关研究，阐明LINC00294通过吸附miR-21-5p促进CASKIN1表达并激活cAMP途径，从而抑制线粒体功能并促进胶质瘤细胞凋亡。 利用拉曼光谱技术采集胶质瘤患者与健康人的血清光谱，通过基于特征工程的分类模型进行预测，实现了对胶质瘤患者的快速、稳定且准确的诊断。