Tumor-associated Tn-MUC1 glycoform is internalized through the macrophage galactose-type C-type lectin and delivered to the HLA class I and II compartments in dendritic cells
Tumor-associated Tn-MUC1 glycoform is internalized through the macrophage galactose-type C-type lectin and delivered to the HLA class I and II compartments in dendritic cells
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DOI：
10.1158/0008-5472.can-07-1035
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Nuti, Marianna
中科院分区：
文献类型：
--
作者：
Napoletano, Chiara;Rughetti, Aurelia;Nuti, Marianna
肿瘤相关抗原与特化抗原呈递细胞（如树突状细胞（DC））之间的相互作用类型对于将产生的免疫类型至关重要。MUC 1是一种高度O-糖基化的粘蛋白，在几种肿瘤组织型中过度表达和异常糖基化。这导致肿瘤相关糖型的表达和携带肿瘤特异性聚糖Tn（GaINAc α 1-O-Ser/Thr）的MUCI。对应于MUCI的三个串联重复的糖肽，用9或15摩尔的GalNAc酶促糖基化，显示特异性结合并被未成熟单核细胞衍生的DC（iDC）内化。结合需要钙和GalNAc残基，并被GalNAc聚合物和Tn-MUC 1或Tn-MUC 2糖肽竞争。在iDC上表达的巨噬细胞半乳糖型C型凝集素（MGL）受体被证明负责结合。对iDC的亚细胞级分进行的共聚焦分析和ELISA显示，Tn-MUC 1糖肽在内化后与HLA I类和II类区室共定位。重要的是，尽管Tn-MUC 1重组蛋白被MGL结合并内化，但糖蛋白进入HLA II类区室，而不是HLA I类通路。这些数据表明，在iDC上表达的MGL是用于将携带免疫原的短GalNAc内化以递送到HLA I类和II类区室中的最佳受体。因此，这样的糖肽代表靶向DC的HLA I类和I t途径的新方式。这些结果可能对癌症疫苗的设计产生影响。
The type of interaction between tumor-associated antigens and specialized antigen-presenting cells such as dendritic cells (DCs) is critical for the type of immunity that will be generated. MUC1, a highly O-glycosylated mucin, is overexpressed and aberrantly glycosylated in several tumor histotypes. This results in the expression of tumor-associated glycoforms and in MUCI carrying the tumor-specific glycan Tn (GaINAc alpha 1-O-Ser/Thr). Glycopeptides corresponding to three tandem repeats of MUCI, enzymatically glycosylated with 9 or 15 mol of GalNAc, were shown to specifically bind and to be internalized by immature monocyte-derived DCs (iDCs). Binding required calcium and the GalNAc residue and was competed out by GalNAc polymer and Tn-MUC1 or Tn-MUC2 glycopeptides. The macrophage galactose-type C-type lectin (MGL) receptor expressed on iDCs was shown to be responsible for the binding. Confocal analysis and ELISA done on subcellular fractions of iDCs showed that the Tn-MUC1 glycopeptides colocalized with HLA class I and II compartments after internalization. Importantly, although Tn-MUC1 recombinant protein was bound and internalized by MGL, the glycoprotein entered the HLA class II compartment, but not the HLA class I pathway. These data indicate that MGL expressed on iDCs is an optimal receptor for the internalization of short GalNAcs carrying immunogens to be delivered into HLA class I and II compartments. Such glycopeptides therefore represent a new way of targeting the HLA class I and It pathways of DCs. These results have possible implications in designing cancer vaccines.