B7-H4在胶质瘤干细胞与微环境内巨噬细胞/小胶质细胞“对话”中的作用研究

Studies have shown the existence of brain tumor stem cells (BTSCs) in gliomas, and it is also known that macrophages (Mφ) / microglia act as primary immune cells in the glioma microenvironment. B7-H4 is a negative costimulatory molecules which plays an important role in the negative regulation of immune responses. Our previous data confirmed BTSCs in gliomas which can escape from immune surveillance by B7-H4 expression. And Mφ / microglias were also found to express B7-H4. The question which we focus on is whether B7-H4 pathway leads to negative immune regulation in the "crosstalk" between BTSCs and Mφ / microglia. We try to clarify which cytokines secreted by BTSCs can induce Mφ / microglia's expression of B7-H4, and identify the role of B7-H4 positive Mφ / microglia in the immune escape of BTSCs in vivo and vitro. Finally,the relationship between patient prognosis and B7-H4 positive Mφ / microglia accumulation density in glioma tissues will be evaluated. The goal of the study will provide useful information for understanding glioma immune suppression mechanisms in depth, searching new targets for effective immune therapy and new biomarkers for the prognosis of glioma patients.

研究表明，脑胶质瘤中存在脑肿瘤干细胞（BTSCs）,且目前已明确巨噬细胞.（Mφ）/小胶质细胞是胶质瘤微环境内主要的免疫细胞。而B7-H4是一种负性共刺激分子，其在免疫应答的负调控中发挥了重要作用。我们前期研究证实胶质瘤中存在BTSCs，其能通过表达B7-H4而逃避机体免疫监视；我们还发现微环境中Mφ/小胶质细胞可表达B7-H4。我们聚焦及感兴趣的问题是：B7-H4途径是否在胶质瘤BTSCs与微环境内Mφ/小胶质细胞相互"对话"中发挥了负性调控作用。我们希望明确BTSCs分泌哪些细胞因子能诱导Mφ/小胶质细胞表达B7-H4；通过体内外实验明确胶质瘤微环境内B7-H4阳性Mφ/小胶质细胞在BTSCs免疫逃逸中的具体作用；明确B7-H4阳性Mφ/小胶质细胞在胶质瘤组织中聚集密度与病人预后的关系，为深入理解胶质瘤免疫抑制机理及寻找有效免疫治疗新靶标、判断患者预后新指标方面积累有用的资料。

巨噬细胞（Mφs）/小胶质细胞（microglia）是胶质母细胞瘤(Glioblastoma,GBM）中浸润的主要免疫细胞，其在肿瘤微环境中被“教育”成免疫抑制性及促进肿瘤生长的M2型巨噬细胞。胶质瘤干细胞（Glioma stem-like cells,GSCs)在GBM发生、进展、复发和放化疗抵抗及免疫抑制方面发挥了中心作用。B7-H4（B7x,B7S1）,是新近发现的T细胞共刺激分子B7家族的新成员，在体内通过抑制T细胞增殖、细胞周期进展和细胞因子产生而负性调节T细胞反应。我们探索了B7-H4信号通路在胶质瘤干细胞诱导肿瘤微环境中M2型Mφs的作用，并进一步对B7-H4+Mφs在肿瘤微环境中的免疫功能进行了探索。我们的研究表明，CD133+肿瘤细胞能诱导肿瘤微环境中的Mφs上调表达B7-H4，同时，B7-H4+的巨噬细胞能通过抑制T细胞的功能及自身吞噬能力下降而形成一个免疫抑制的微环境。GSCs和肿瘤微环境中的Mφs上的B7-H4分子可能是今后胶质瘤免疫治疗新的靶标。