Ceramide structure predicts tumor ganglioside immunosuppressive activity.

Molecular determinants of biological activity of gangliosides are generally believed to be carbohydrate in nature. However, our studies of immunomodulation by highly purified naturally occurring tumor gangliosides provide another perspective: while the immunosuppressive activity of gangliosides requires the intact molecule (both carbohydrate and ceramide moieties), ceramide structure strikingly influences ganglioside immunosuppressive activity. Molecular species of human neuroblastoma GD2 ganglioside in which the ceramide contains a shorter fatty acyl chain (C16:0, C18:0) were 6- to 10-fold more active than those with a longer fatty acyl chain (C22:0/C24:1, C24:0). These findings were confirmed in studies of ceramide species of human leukemia sialosylparagloboside and murine lymphoma GalNAcGM1b. Gangliosides that contain shorter-chain fatty acids (and are most immunosuppressive) are known to be preferentially shed by tumor cells. Therefore, the results suggest that the tumor cell is optimized to protect itself from host immune destruction by selective shedding of highly active ceramide species of gangliosides. IMAGES:

一般认为，神经节苷脂（gangliosides）生物活性的分子决定簇本质上为碳水化合物。然而，我们针对高纯度天然肿瘤神经节苷脂开展的免疫调节研究给出了不同视角：尽管神经节苷脂的免疫抑制活性需要完整的分子结构（同时包含碳水化合物与神经酰胺结构域），但神经酰胺的结构会显著影响神经节苷脂的免疫抑制活性。
针对人神经母细胞瘤GD2神经节苷脂（GD2 ganglioside）的分子亚型研究显示，其神经酰胺携带较短脂肪酰基链（C16:0、C18:0）的亚型，免疫抑制活性是携带较长脂肪酰基链（C22:0/C24:1、C24:0）亚型的6至10倍。
上述发现已在人白血病唾液酰基副 globoside（sialosylparagloboside）以及鼠淋巴瘤GalNAcGM1b神经节苷脂的相关研究中得到验证。
已知含短链脂肪酸且免疫抑制活性最强的神经节苷脂会被肿瘤细胞优先脱落释放。因此，本研究结果提示，肿瘤细胞可通过选择性脱落高活性神经酰胺亚型神经节苷脂，优化自身免疫逃逸机制，躲避宿主免疫系统的杀伤。
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