Bennaceur Karim, Popa Iuliana, Portoukalian Jacques, Berthier-Vergnes Odile, Péguet-Navarro Josette
EA 37-32, Clinique Dermatologique, Pavillon R, Hôpital E. Herriot, Université Claude Bernard Lyon 1, 69437 Lyon Cedex 03, France.
Int Immunol. 2006 Jun;18(6):879-86. doi: 10.1093/intimm/dxl024. Epub 2006 May 4.
Gangliosides are ubiquitous, membrane-associated, glycosphingolipids, 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.
神经节苷脂是普遍存在的、与膜相关的糖鞘脂，其组成和产生在许多肿瘤细胞中会发生改变。已表明它们能抑制祖细胞在体外生成和分化为树突状细胞（DC），但它们对人体组织驻留DC的影响尚待研究。在本研究中，我们分析了从人黑色素瘤肿瘤中纯化的GM3和GD3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，这两种神经节苷脂均损害了短期体外培养诱导的LC自发成熟，这通过共刺激分子（CD40、CD54、CD80、CD86）和成熟标志物（CD83、CCR7）的显著下调来评估，这与细胞引发同种异体T细胞增殖的能力受损相关。此外，经神经节苷脂处理的细胞向CCL19/巨噬细胞炎性蛋白3β迁移的能力降低，CCL19/巨噬细胞炎性蛋白3β是一种特异性结合CCR7并介导LC迁移至淋巴结的趋化因子。最后，我们表明GM3和GD3神经节苷脂均增强了LC的自发凋亡。总体而言，这些体外研究结果可能至少部分解释了黑色素瘤患者体内LC数量和分布的改变。它们强调了神经节苷脂通过在肿瘤微环境中诱导LC功能障碍来阻碍宿主免疫反应的新机制。
