Induction of HLA-A2-restricted CTLs to the mucin 1 human breast cancer antigen.
HLA-A*0201/Kb transgenic mice were immunized with oxidized mannan-mucin 1 (MUC1) as a fusion protein (containing five repeats of the 20-amino-acid MUC1 VNTR (variable number of tandem repeats) that generated highly active CD8+ CTLs to MUC1 peptides. In a direct CTL assay, the MUC1 peptides could be presented specifically by both the transgenic murine HLA-A*0201/Kb and human HLA-A*0201 molecules. The 9-mer MUC1 peptide sequences (APDTRPA and STAPPAHGV) were presented by HLA-A*0201, although they did not contain L at P2 and L/V at P9, the preferred motifs; as a consequence, the binding was of relatively low affinity when compared with a high affinity-binding HIV peptide (ILKEPVHGV). In addition, when mice were immunized separately with the HLA-A*0201-binding peptides (STAPPAHGV or APDTRPAP-containing peptides-keyhole limpet hemocyanin-mannan), direct lysis of MCF-7 (HLA-A*0201+, MUC1+) also occurred. The findings are of interest for tumor immunotherapy, particularly as the CTLs generated to low affinity-binding peptides were highly active and could specifically lyse an HLA-A*0201+ human breast cancer cell line without further in vitro stimulation. The findings demonstrate that the range of peptides that can generate CTLs is broader than formerly considered.
Apostolopoulos
V
V
The Austin Research Institute, Heidelberg, Victoria, Australia.
Karanikas
V
V
Haurum
J S
JS
McKenzie
I F
IF
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001943:Breast Neoplasms / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D000939:Epitopes; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology*; D010455:Peptides; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000939:Epitopes; D015789:HLA-A2 Antigen; D018396:Mucin-1; D010455:Peptides