Abstract
The identification of tumor-associated T cell epitopes has contributed significantly to the understanding of the interrelationship of tumor and immune system and is instrumental in the development of therapeutic vaccines for the treatment of cancer. Most of the known epitopes have been identified with prediction algorithms that compute the potential capacity of a peptide to bind to HLA class I molecules. However, naturally expressed T cell epitopes need not necessarily be strong HLA binders. To overcome this limitation of the available prediction algorithms we established a strategy for the identification of T cell epitopes that include suboptimal HLA binders. To this end, an artificial neural network was developed that predicts HLA-binding peptides in protein sequences by taking the entire sequence context into consideration rather than computing the sum of the contribution of the individual amino acids. Using this algorithm, we predicted seven HLA A*0201-restricted potential T cell epitopes from known melanoma-associated Ags that do not conform to the canonical anchor motif for this HLA molecule. All seven epitopes were validated as T cell epitopes and three as naturally processed by melanoma tumor cells. T cells for four of the new epitopes were found at elevated frequencies in the peripheral blood of melanoma patients. Modification of the peptides to the canonical sequence motifs led to improved HLA binding and to improved capacity to stimulate T cells.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / metabolism
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Antigens, Neoplasm / therapeutic use
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cancer Vaccines / immunology*
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Cancer Vaccines / metabolism
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Cancer Vaccines / therapeutic use*
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Cell Line
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Cell Line, Tumor
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Computational Biology / methods
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Cytotoxicity Tests, Immunologic / methods
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Enzyme-Linked Immunosorbent Assay / methods
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Epitopes, T-Lymphocyte / immunology*
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Epitopes, T-Lymphocyte / metabolism
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Epitopes, T-Lymphocyte / therapeutic use*
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HLA-A Antigens / biosynthesis
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HLA-A Antigens / immunology
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HLA-A Antigens / metabolism
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HLA-A2 Antigen
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Humans
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Melanoma / immunology*
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Melanoma / therapy*
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Melanoma-Specific Antigens
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / therapeutic use
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Neoplasm Proteins / immunology*
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / therapeutic use*
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Predictive Value of Tests
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Protein Binding / immunology
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gp100 Melanoma Antigen
Substances
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Antigens, Neoplasm
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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HLA-A Antigens
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HLA-A*02:01 antigen
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HLA-A2 Antigen
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MAGEA1 protein, human
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Mage-a2 antigen
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Melanoma-Specific Antigens
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Membrane Glycoproteins
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Neoplasm Proteins
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PMEL protein, human
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Peptide Fragments
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gp100 Melanoma Antigen