Identification of O-glycosylated decapeptides within the MUC1 repeat domain as potential MHC class I (A2) binding epitopes

Tanja Ninkovic, Leo Kinarsky, Katja Engelmann, Vladimir Pisarev, Simon Sherman, Olivera J. Finn, Franz Georg Hanisch

Research output: Contribution to journalReview article

32 Citations (Scopus)

Abstract

The MUC1 glycoprotein is considered a tumor antigen due to its over expression and aberrant glycosylation in cancer tissues. The latter results in appearance of new antigenic tumor specific glycopeptides not found on normal glycoforms of the mucin. MUC1 glycopeptides can be presented by APCs on MHC class II molecules to activate glycopeptide specific helper T-cells. No study has yet reported presentation of MUC1 glycopeptides on MHC class I molecules as stimulators of cytotoxic T-cells. In this study we show that human immunoproteasomes and cathepsin-L can generate octa to undecameric glycopeptides from the MUC1 repeat domain in vitro. We identified glycosylated fragments of which the decameric glycopeptide SAP10 [SAPDT(GalNAc)RPAPG] containing a single sugar binds with comparable strength to the MHC class I allele HLA A*0201 as predicted high-score binding epitopes of the tandem repeat. The same sequence glycosylated with the disaccharide Gal-GalNAc does not bind. The glycan on SAP10 is predicted by molecular modeling to either protrude out or point into the MHC groove. SAPDTRPAPG peptide and the respective glycopeptide stimulated cytotoxic T-cells in vitro. Our findings suggest that MUC1 tandem repeat glycopeptides are capable of activating both helper and cytotoxic T-cells and thus represent good candidates for further development as vaccines.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalMolecular Immunology
Volume47
Issue number1
DOIs
StatePublished - Nov 1 2009

Fingerprint

Glycopeptides
varespladib methyl
Epitopes
Tandem Repeat Sequences
Helper-Inducer T-Lymphocytes
T-Lymphocytes
Cathepsin L
Disaccharides
Neoplasm Antigens
Mucins
Glycosylation
Polysaccharides
Neoplasms
Glycoproteins
Vaccines
Alleles
Peptides

Keywords

  • Cancer vaccine
  • Cathepsin-L
  • Immunoproteasome
  • MHC class I
  • MUC1

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

Cite this

Identification of O-glycosylated decapeptides within the MUC1 repeat domain as potential MHC class I (A2) binding epitopes. / Ninkovic, Tanja; Kinarsky, Leo; Engelmann, Katja; Pisarev, Vladimir; Sherman, Simon; Finn, Olivera J.; Hanisch, Franz Georg.

In: Molecular Immunology, Vol. 47, No. 1, 01.11.2009, p. 131-140.

Research output: Contribution to journalReview article

Ninkovic, Tanja ; Kinarsky, Leo ; Engelmann, Katja ; Pisarev, Vladimir ; Sherman, Simon ; Finn, Olivera J. ; Hanisch, Franz Georg. / Identification of O-glycosylated decapeptides within the MUC1 repeat domain as potential MHC class I (A2) binding epitopes. In: Molecular Immunology. 2009 ; Vol. 47, No. 1. pp. 131-140.
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