Ganglioside DSGb5, preferred ligand for Siglec-7, inhibits NK cell cytotoxicity against renal cell carcinoma cells
Ganglioside DSGb5, preferred ligand for Siglec-7, inhibits NK cell cytotoxicity against renal cell carcinoma cells
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DOI：
10.1093/glycob/cwq116
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发表时间：
2010-11-01
期刊：
影响因子：
4.3
通讯作者：
Arai, Yoichi
中科院分区：
文献类型：
--
作者：
Kawasaki, Yoshihide;Ito, Akihiro;Arai, Yoichi
在肾细胞癌（RCC）中，较高的神经节苷脂的存在与系统性转移相关。DSGb 5是肾细胞癌组织中主要的神经节苷脂之一。Siglec-7（唾液酸结合免疫球蛋白样凝集素-7）作为抑制性受体在自然杀伤（NK）细胞上表达，对内部分支的α 2，6连接的二唾液酸神经节苷脂（例如DSGb 5）具有显着的偏好。为了阐明DSGb 5在RCC转移中的功能作用，我们研究了在RCC细胞上表达的DSGb 5是否可以以Siglec-7依赖性方式调节NK细胞的细胞毒性。抗DSGb 5单克隆抗体和转染针对DSGb 5合成酶ST 6 GalNAcVI的siRNA可特异性抑制RCC细胞与Siglec-7-Fc融合蛋白的结合活性。这些观察结果表明Siglec-7-Fc融合蛋白特异性结合RCC细胞上表达的DSGb 5。相比之下，NK细胞上Siglec-7的唾液酸结合位点通过与细胞表面的内源性唾液酸缀合物的顺式相互作用而被掩蔽，但其可以通过NK细胞的唾液酸酶处理而被揭开。在NK细胞的唾液酸酶处理后，NK细胞对具有高DSGb 5表达的RCC细胞的细胞毒性相对于具有低DSGb 5表达的细胞显著降低。这些发现表明，效应细胞上的Siglec-7和靶细胞上的DSGb 5之间的相互作用可以抑制针对RCC细胞的这种NK细胞细胞毒性。本研究的结果表明，在RCC细胞上表达的DSGb 5可以以DSGb 5-Siglec-7依赖性方式下调NK细胞的细胞毒性，并且具有DSGb 5的RCC细胞为其自身的存活和转移创造了有利的环境。
In renal cell carcinoma (RCC), the presence of higher gangliosides correlates with systematic metastasis. Disialosyl globopentaosylceramide (DSGb5) was identified previously as one of the major gangliosides from RCC tissues. Siglec-7 (sialic acid-binding Ig-like lectin-7), expressed on natural killer (NK) cells as an inhibitory receptor, has a striking preference for internally branched alpha 2,6-linked disialic gangliosides such as DSGb5. To clarify the functional role of DSGb5 in RCC metastases, we have investigated whether DSGb5 expressed on RCC cells can modulate NK cell cytotoxicity in a Siglec-7-dependent manner. The binding activity of RCC cells to Siglec-7-Fc fusion protein was specifically inhibited by anti-DSGb5 monoclonal antibody and transfection of siRNA for ST6GalNAcVI (synthetase of DSGb5). These observations showed that Siglec-7-Fc fusion protein specifically bound to DSGb5 expressed on RCC cells. In contrast, the sialic acid-binding site of Siglec-7 on NK cells was masked by cis interactions with endogenous sialoconjugates at the cell surface, but it could be unmasked by sialidase treatment of the NK cells. Following sialidase treatment of NK cells, NK cell cytotoxicity against RCC cells with high DSGb5 expression was significantly decreased relative to cells with low DSGb5 expression. These findings indicate that such NK cell cytotoxicity against RCC cells could be inhibited by the interaction between Siglec-7 on effecter cells and DSGb5 on target cells. The results of the present study suggest that DSGb5 expressed on RCC cells can downregulate NK cell cytotoxicity in a DSGb5-Siglec-7-dependent manner and that RCC cells with DSGb5 create favorable circumstance for their own survival and metastases.