基于Hedgehog通路调控的共刺激分子"4IgB7H3"在胶质瘤细胞免疫逃逸中的分子机理研究

Glioma is the most common primary brain tumor, and the effect of conventional treatment is poor, One of the possible causes of which is immune escape.The literature and previous research suggest that abnormal activation of Hedgehog (Hh) pathway in glioma can inhibit apoptosis through Fas/FasL/Caspases pathway that is also one of the mechanisms of NK cells' killing tumor cells.Costimulatory molecule 4IgB7H3 inhibits the killing effect of NK cell, and we guess the mechanisms of this kind of inhibition is related to Fas /FasL /Caspases pathway.Further hypothesis is that in glioma cells, Hh pathway regulates 4IgB7H3 through inhibiting the killing effect of NK cell.The demonstration should be finished as follow: the relationship between expression of 4IgB7H3 and Fas /FasL /Caspases in glioma; the inhibition of 4IgB7H3 against the activity of NK cells to kill the glioma cells through Fas /FasL /Caspases pathway; 4IgB7H3 is regulated by Hh pathway so that the ability of tumor cells escape immune is promoted.In this study, the possible mechanism that Hh pathway promote the immune escape of glioma through 4IgB7H3 beiing regulated will be discussed.The theory basis to understand how signaling pathways mediate glioma immune escape ,new ideas and intervention targets for glioma immunotherapy will be provided.

胶质瘤是最常见的原发脑肿瘤，常规治疗效果差，免疫逃逸是可能原因之一。文献和前期研究提示胶质瘤中异常活化的Hedgehog（Hh）通路通过影响Fas/FasL/Caspases途径发挥抗凋亡作用，该途径也是NK细胞杀伤肿瘤细胞的机制之一。共刺激分子4IgB7H3抑制NK细胞的杀伤效应，猜测抑制作用与Fas /FasL /Caspases途径有关；进一步假设： Hh通路调控4IgB7H3，抑制NK细胞杀伤胶质瘤细胞的作用。拟论证：胶质瘤中4IgB7H3表达和Fas /FasL /Caspases的关系；4IgB7H3通过Fas /FasL /Caspases途径影响NK细胞对胶质瘤细胞的杀伤作用；Hh通路调控4IgB7H3促进胶质瘤细胞免疫逃逸。本研究探讨Hh通路调节4IgB7H3促进胶质瘤免疫逃逸的可能机制，为理解信号通路介导胶质瘤免疫逃逸提供理论依据，为胶质瘤免疫治疗提供新思路和干预靶点。

胶质瘤是中枢神经系统最常见、治疗效果最差的肿瘤之一。胶质瘤易复发、对放化疗均不敏感，因而有必要探索治疗胶质瘤的新思路。由于中枢神经系统免疫微环境的特殊性和胶质瘤本身存在免疫缺陷性，胶质瘤免疫治疗效果并不理想，可能与胶质瘤免疫逃逸有关。本项目应用分子生物学技术研究胶质瘤U251细胞中4IgB7H3与Fas /FasL /Caspases途径的作用关系；比较Hh通路在不同活化状态下，4IgB7H3表达水平是否具有差异性。进一步探讨Hh通路通过调控4IgB7H3，抑制NK细胞对胶质瘤细胞的杀伤效应的具体机制。研究结果显示：（1）异常活化的Hh 通路调控4IgB7H3介导的胶质瘤免疫逃逸，Hh通路在不同活化状态下，4IgB7H3表达水平具有差异性。（2）胶质瘤细胞诱导Fas/Fasl异常活化造成对免疫细胞的打击；进一步探讨Hh通路通过调控4IgB7H3，抑制NK细胞对胶质瘤细胞的杀伤效应的具体机制。Fas被敲除后，NK细胞对U251细胞的杀伤活性下降最明显。IFN-γ与肿瘤细胞表面MICA/B的表达具有相关性。（3）首次发现4IgB7H3下游基因UBE2S是胶质瘤发展、转移的重要基因，目前未见报告，为胶质瘤的精准治疗提供了一个可能的靶点。