TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia
TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia
复制标题
TLR2 通过下调小胶质细胞中 MHC II 类分子促进胶质瘤免疫逃避。
DOI：
10.1158/2326-6066.cir-18-0020
复制
发表时间：
2018-10-01
影响因子：
10.1
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Qian, Jiawen;Luo, Feifei;Chu, Yiwei
神经胶质瘤是脑内最常见的原发性肿瘤，因其逃避免疫反应的能力而臭名昭著。尽管在神经胶质瘤中存在小胶质细胞浸润，但这些小胶质细胞中MHC II类分子的表达受到损害。在这里，我们报告说，Toll样受体2（TLR 2）激活下调表达的MHC II类分子在小胶质细胞原位小鼠胶质瘤模型。TLR 2诱导的小胶质细胞损伤阻碍了CD 4（+）T细胞的增殖和活化，从而促进了胶质瘤的免疫逃避。TLR 2诱导的MHC II类分子的下调是由抑制MHC II类分子转录的主调节因子Ciita引起的。TLR 2激活触发下游MAPK/ERK 1/2信号传导和Ciita启动子处组蛋白H3乙酰化的丧失，这反过来抑制Ciita表达。在胶质母细胞瘤组织中，各种内源性TLR 2配体，包括作为内源性TLR 2配体的热休克蛋白，被上调，这是与CIITA抑制相关的反应。因此，TLR 2促进胶质瘤免疫逃逸。这些结果推进了我们对小胶质细胞在胶质瘤中作为抗原呈递细胞的理解。在神经胶质瘤肿瘤微环境中，小胶质细胞的TLR 2活化诱导小胶质细胞MHC II类表达下调。受损的MHC II类表达限制T细胞依赖性抗肿瘤免疫。
Gliomas, the most common primary neoplasms in the brain, are notorious for their ability to evade the immune response. Despite microglial infiltration in gliomas, expression of MHC class II molecules in those microglia is compromised. Here, we report that Toll-like receptor 2 (TLR2) activation downregulated expression of MHC class II molecules in microglia in an orthotopic murine glioma model. TLR2-induced microglial impairment hindered the proliferation and activation of CD4(+) T cells, which facilitated glioma immune evasion. TLR2-induced downregulation of MHC class II molecules was caused by suppression of the master regulator of MHC class II molecule transcription, Ciita. TLR2 activation triggered downstream MAPK/ERK1/2 signaling and loss of histone H3 acetylation at Ciita promoters, which in turn inhibited Ciita expression. In glioblastoma tissues, various endogenous TLR2 ligands, including the heat shock proteins that are endogenous TLR2 ligands, were upregulated, a response that correlated with CIITA inhibition. Thus, TLR2 promotes glioma immunesystem evasion. These results advance our understanding of microglia as antigen-presenting cells in the context of glioma. In the glioma tumor microenvironment, TLR2 activation of microglia induces downregulation of microglial MHC class II expression. Impaired MHC class II expression limits T-cell-dependent antitumor immunity.