Identification of New Epitopes from Four Different Tumor-Associated Antigens: Recognition of Naturally Processed Epitopes Correlates with HLA-A∗0201-Binding Affinity
| Autor: | Scott Southwood, John Fikes, Elissa Keogh, Robert W. Chesnut, Esteban Celis, Alessandro Sette |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Receptor ErbB-2 T cell Immunology Antigen presentation Epitopes T-Lymphocyte Human leukocyte antigen Biology Lymphocyte Activation Epitope Antigen Antigens Neoplasm HLA-A2 Antigen Tumor Cells Cultured medicine Humans Immunology and Allergy Alleles Cells Cultured Cell Line Transformed Antigen Presentation Immunogenicity Cytotoxicity Tests Immunologic Molecular biology Peptide Fragments In vitro Carcinoembryonic Antigen Neoplasm Proteins CTL medicine.anatomical_structure Amino Acid Substitution Female Tumor Suppressor Protein p53 Protein Binding T-Lymphocytes Cytotoxic |
| Zdroj: | The Journal of Immunology. 167:787-796 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.167.2.787 |
| Popis: | Forty-two wild-type and analogue peptides derived from p53, carcinoembryonic Ag, Her2/neu, and MAGE2/3 were screened for their capacity to induce CTLs, in vitro, capable of recognizing tumor target lines. All the peptides bound HLA-A*0201 and two or more additional A2 supertype alleles with an IC50 of 500 nM or less. A total of 20 of 22 wild-type and 9 of 12 single amino acid substitution analogues were found to be immunogenic in primary in vitro CTL induction assays, using normal PBMCs and GM-CSF/IL-4-induced dendritic cells. These results suggest that peripheral T cell tolerance does not prevent, in this system, induction of CTL responses against tumor-associated Ag peptides, and confirm that an HLA class I affinity of 500 nM or less is associated with CTL epitope immunogenicity. CTLs generated by 13 of 20 of the wild-type epitopes, 6 of 9 of the single, and 2 of 5 of the double substitution analogues tested recognized epitopes generated by endogenous processing of tumor-associated Ags and expressed by HLA-matched cancer cell lines. Further analysis revealed that recognition of naturally processed Ag was correlated with high HLA-A2.1-binding affinity (IC50 = 200 nM or less; p = 0.008), suggesting that high binding affinity epitopes are frequently generated and can be recognized as a result of natural Ag processing. These results have implications for the development of cancer vaccines, in particular, and for the process of epitope selection in general. |
| Databáze: | OpenAIRE |
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