MUC1-derived glycopeptide libraries with improved MHC anchors are strong antigens and prime mouse T cells for proliferative responses to lysates of human breast cancer tissue.
Multi-component glycopeptide libraries and single glycopeptides were used for immunization of mice with the aim of inducing strong T helper cell responses to the repetitive sequence of MUC1 expressed by human tumor cells. The glycopeptides and glycopeptide libraries were modeled upon the native human MUC1 amino acid variable number of tandem repeats sequence by introduction of modifications in the MHC anchor positions to optimally fulfil the binding requirements of the A(d) MHC class II molecule in the BALB/c mouse. The immunogenicity of the MUC1 glycopeptides in BALB/c mice was determined by immunization in complete Freund's adjuvant and assaying lymph node T cells for a proliferative response to the glycopeptide used. Strong proliferative responses with stimulation indices over 50 were obtained with anchor-improved glycopeptide libraries as well as with single glycopeptides. Immunization with one of the glycopeptide libraries primed T cells for a proliferative cross-response to the native MUC1 glycopeptide, which by itself was nonimmunogenic. In addition, immunization with the same glycopeptide library primed T cells for a strong response to lysate of a MUC1-expressing human breast cancer, and immunization with the tumor lysate primed T cells for a response to the glycopeptide library. The T cells responding in the assay for proliferation were restricted to the A(d) MHC class II molecule. The results indicate that immunization with MHC anchor-improved MUC1 glycopeptide libraries can effectively prime T helper cells and may induce long-term memory. The approach may be useful in the design of preventive cancer vaccines for use in humans.
Gad
Monika
M
Institute for Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Jensen
Teis
T
Gagne
Rod
R
Komba
Shiro
S
Daugaard
Søren
S
Kroman
Niels
N
Meldal
Morten
M
Werdelin
Ole
O
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006020:Glycopeptides / Q000276:immunology*; D006031:Glycosylation; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D019151:Peptide Library; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014020:Tissue Extracts / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006020:Glycopeptides; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D019151:Peptide Library; D014020:Tissue Extracts