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

Chiara Napoletano, Aurelia Rughetti, Mads P. Agervig Tarp, Julia Coleman, Eric P. Bennett, Gianfranco Picco, Patrizio Sale, Kaori Denda-Nagai, Tatsuro Irimura, Ulla Mandel, Henrik Clausen, Luigi Frati, Joyce Taylor-Papadimitriou, Joy Burchell, Marianna Nuti

Research output: Contribution to journalArticlepeer-review

Abstract

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 MUC1 carrying the tumor-specific glycan Tn (GalNAcα1-O-Ser/Thr). Glycopeptides corresponding to three tandem repeats of MUC1, 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 II pathways of DCs. These results have possible implications in designing cancer vaccines.

Original languageEnglish
Pages (from-to)8358-8367
Number of pages10
JournalCancer Research
Volume67
Issue number17
DOIs
Publication statusPublished - Sep 1 2007

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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