Abstract
The MUC1 protein was found to be up-regulated in a spectrum of malignant tumors. T-cell responses to the MUC1 extracellular tandem repeat array (TRA) were observed in murine models as well as in breast-carcinoma patients. In the present study, we evaluated the anti-tumor potential of HLA-A2.1-motif-selected peptides from non-TRA domains of the molecule. Peptide immunogenicity was examined in the Db-/- x beta2 microglobulin (beta2m) null mice transgenic for a modified HLA-A2.1/Db-beta2 microglobulin single chain (HHD mice). Our results show the existence of 3 novel HLA-A2.1-restricted MUC1-derived cytotoxic T-lymphocyte (CTL) epitopes. These peptides are processed and presented by the HHD-transfected breast-tumor cell line MDA-MB-157. Moreover, CTL induced by these 3 peptides show higher lysis of target cells pulsed with breast-carcinoma-derived peptides than of targets pulsed with normal breast-tissue-derived peptides. These data suggest an important role for non-TRA MUC1-derived peptides as inducers of a MHC-restricted CTL reaction to a breast-carcinoma cell line and patient-derived tumor extracts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen Presentation
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Breast Neoplasms / immunology*
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Breast Neoplasms / metabolism
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Cancer Vaccines / chemistry
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology*
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Cytotoxicity, Immunologic
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Epitopes, T-Lymphocyte / chemistry
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Epitopes, T-Lymphocyte / immunology*
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Female
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Fluorescence
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Gene Expression Regulation, Neoplastic
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H-2 Antigens / genetics
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H-2 Antigens / immunology
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HLA-A2 Antigen / immunology*
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Histocompatibility Antigen H-2D
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mucin-1 / chemistry
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Mucin-1 / immunology*
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Mucin-1 / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / immunology*
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Peptide Fragments / metabolism
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Peptides / immunology
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Protein Binding
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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T-Lymphocytes, Cytotoxic / immunology*
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Tumor Cells, Cultured
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beta 2-Microglobulin / chemistry
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beta 2-Microglobulin / genetics
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beta 2-Microglobulin / immunology*
Substances
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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H-2 Antigens
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HLA-A2 Antigen
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Histocompatibility Antigen H-2D
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MUC1 tandem repeat peptide
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Mucin-1
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Peptide Fragments
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Peptides
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Recombinant Fusion Proteins
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beta 2-Microglobulin