Tumor-associated MUC1 glycopeptide epitopes are not subject to self-tolerance and improve responses to MUC1 peptide epitopes in MUC1 transgenic mice.
Human adenocarcinomas overexpress a hypoglycosylated, tumor-associated form of the mucin-like glycoprotein MUC1 containing abnormal mono- and disaccharide antigens, such as Tn, sialyl-Tn, and TF, as well as stretches of unglycosylated protein backbone in the variable number of tandem repeats (VNTR) region. Both peptide and glycopeptide epitopes generated from the VNTR are candidates for cancer vaccines and we performed experiments to evaluate their relative potential to elicit tumor-MUC1-specific immunity. We show here that immunization with the 100 amino acid-long VNTR peptide (MUC1p) elicits weaker responses in MUC1 transgenic mice compared to wild type mice suggesting self-tolerance. In contrast, when glycosylated with tumor-associated Tn antigen (GalNAc-O-S/T), TnMUC1 induces glycopeptide-specific T cell and antibody responses in both strains of mice and helps enhance responses to MUC1p in MUC1 transgenic mice. Using newly derived MUC1-specific mouse T cell hybridomas we show that the only antigen-presenting cells able to cross-present TnMUC1 glycopeptide are dendritic cells (DCs). This is likely due to their exclusive expression of receptors capable of binding TnMUC1. We conclude that MUC1 glycopeptides induce stronger immunity in MUC1-Tg mice because they are recognized as 'foreign' rather than ;self' and because they are cross-presented preferentially by DCs.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Sean O
SO
Ryan
Anda M
AM
Vlad
Kazi
K
Islam
Jean
J
Gariépy
Olivera J
OJ
Finn
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D017951:Antigen Presentation / Q000276:immunology; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D006020:Glycopeptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006031:Glycosylation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
D015295:Antigens, Tumor-Associated, Carbohydrate; D000939:Epitopes; D006020:Glycopeptides; D018396:Mucin-1; C040286:Tn antigen