The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses
The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses
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DOI：
10.1215/15228517-2006-008
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发表时间：
2006-07-01
期刊：
影响因子：
15.9
通讯作者：
Heimberger, Amy B.
中科院分区：
文献类型：
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作者：
Hussain, S. Farzana;Yang, David;Heimberger, Amy B.
关于神经胶质瘤患者中枢神经系统小胶质细胞/巨噬细胞的免疫表现及相互作用知之甚少。我们发现小胶质细胞/巨噬细胞是浸润神经胶质瘤的主要免疫细胞（约占总细胞的1%）；还发现的其他细胞有髓样树突状细胞、浆细胞样树突状细胞和T细胞。我们从神经胶质瘤患者术后组织标本中分离并分析了CD11b/c⁺CD45⁺神经胶质瘤浸润小胶质细胞/巨噬细胞（GIMs）的免疫功能。尽管GIMs表达大量的Toll样受体（TLRs），但它们似乎未被刺激产生促炎细胞因子（肿瘤坏死因子α、白细胞介素1或白细胞介素6），并且在体外，脂多糖能够结合TLR - 4，但不能诱导GIM介导的T细胞增殖。尽管表面表达主要组织相容性复合体II类分子，但它们缺乏对T细胞激活至关重要的共刺激分子CD86、CD80和CD40的表达。在体外，我们证实效应/活化T细胞相应缺乏，因为神经胶质瘤浸润的CD8⁺T细胞表型为CD8⁺CD25⁻。相比之下，有大量调节性CD4 T细胞（CD4⁺CD25⁺FOXP3⁺）浸润肿瘤。我们得出结论，虽然GIMs可能具有一些完整的先天免疫功能，但它们通过TLRs被刺激、分泌细胞因子、上调共刺激分子以及进而激活抗肿瘤效应T细胞的能力不足以启动免疫反应。此外，调节性T细胞的存在可能也导致了针对恶性人类神经胶质瘤缺乏有效的免疫激活。
Little is known about the immune performance and interactions of CNS microglia/macrophages in glioma patients. We found that microglia/macrophages were the predominant immune cell infiltrating gliomas (similar to 1% of total cells); others identified were myeloid dendritic cells (DCs), plasmacytoid DCs, and T cells. We isolated and analyzed the immune functions of CD11b/c+CD45+ glioma-infiltrating microglia/macrophages (GIMs) from postoperative tissue specimens of glioma patients. Although GIMs expressed substantial levels of Toll-like receptors (TLRs), they did not appear stimulated to produce pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin 1, or interleukin 6), and in vitro, lipopolysaccharides could bind TLR-4 but could not induce GIM-mediated T-cell proliferation. Despite surface major histocompatibility complex class 11 expression, they lacked expression of the costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation. Ex vivo, we demonstrate a corresponding lack of effector/activated T cells, as glioma-infiltrating CD8+ T cells were phenotypically CD8+CD25-. By contrast, there was a prominent population of regulatory CD4 T cells (CD4+CD25+FOXP3+) infiltrating the tumor. We conclude that while GIMs may have a few intact innate immune functions, their capacity to be stimulated via TLRs, secrete cytokines, upregulate costimulatory molecules, and in turn activate antitumor effector T cells is not sufficient to initiate immune responses. Furthermore, the presence of regulatory T cells may also contribute to the lack of effective immune activation against malignant human gliomas.