Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis
Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis
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DOI：
10.1093/intimm/dxl024
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Peguet-Navarro, Josette
中科院分区：
文献类型：
--
作者：
Bennaceur, Karim;Popa, Iuliana;Peguet-Navarro, Josette
神经节苷脂是普遍存在的膜相关鞘糖脂，其组成和生产在许多肿瘤细胞中发生改变。它们已经显示出抑制树突状细胞（DC）从祖细胞的体外生成和分化，但它们对人类组织驻留的DC的作用尚待研究。在本研究中，我们分析了从人黑色素瘤肿瘤中纯化的GM 3和GD 3神经节苷脂对人表皮朗格汉斯细胞（LC）的表型和功能成熟的影响，LC是对抗肿瘤细胞的第一道免疫屏障。我们发现，两种神经节苷脂损害自发LC成熟诱导一个短的体外培养，作为评估的共刺激（CD 40，CD 54，CD 80，CD 86）和成熟标志物（CD 83，CCR 7），这与受损的能力的细胞安装同种异体T细胞增殖的显着下调。此外，神经节苷脂处理的细胞显示出向CCL 19/巨噬细胞炎性蛋白3 β迁移的能力较低，CCL 19/巨噬细胞炎性蛋白3 β是特异性结合CCR 7并介导LC迁移至淋巴结的趋化因子。最后，我们发现，GM 3和GD 3神经节苷脂增强LC自发凋亡。在全球范围内，这些体外结果可能至少部分解释了黑色素瘤患者LC数量和分布的改变。他们强调了神经节苷脂通过诱导肿瘤微环境中的LC功能障碍来阻碍宿主免疫反应的新机制。
Gangliosides are ubiquitous, membrane-associated, glycosphingoliplids, the composition and production of which is altered in many tumour cells. They have been shown to inhibit the in vitro generation and differentiation of dendritic cells (DCs) from progenitors, but their effect on human tissue-residing DCs is yet to be investigated. In the present study, we analysed the effect of GM3 and GD3 gangliosides purified from human melanoma tumours on the phenotypic and functional maturation of human epidermal Langerhans cells (LCs), the first immune barrier against the tumour cells. We showed that both gangliosides impaired spontaneous LC maturation induced by a short in vitro culture, as assessed by significant down-regulation of co-stimulation (CD40, CD54, CD80, CD86) and maturation markers (CD83, CCR7), which correlated to an impaired ability of the cells to mount allogeneic T cell proliferation. Furthermore, the ganglioside-treated cells displayed less ability to migrate towards CCL19/macrophage inflammatory protein 3 beta, the chemokine that specifically binds CCR7 and mediates LC migration to lymph nodes. Lastly, we showed that both GM3 and GD3 gangliosides enhance LC spontaneous apoptosis. Globally, these in vitro results might explain, at least in part, the altered number and distribution of LCs in melanoma-bearing patients. They underscore a new mechanism for gangliosides to impede the host immune response by inducing LC dysfunction in the tumour microenvironment.