Identification of new epitopes from four different tumor-associated antigens: Recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity

E. Keogh, J. Fikes, S. Southwood, E. Celis, R. Chesnut, A. Sette

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)787-796
Number of pages10
JournalJournal of Immunology
Volume167
Issue number2
DOIs
StatePublished - Jul 15 2001
Externally publishedYes

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Neoplasm Antigens
Epitopes
Peptides
Inhibitory Concentration 50
Neoplasms
Cancer Vaccines
Amino Acid Substitution
Granulocyte-Macrophage Colony-Stimulating Factor
varespladib methyl
Interleukin-4
Dendritic Cells
Alleles
HLA-A*02:01 antigen
T-Lymphocytes
Cell Line
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Identification of new epitopes from four different tumor-associated antigens : Recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. / Keogh, E.; Fikes, J.; Southwood, S.; Celis, E.; Chesnut, R.; Sette, A.

In: Journal of Immunology, Vol. 167, No. 2, 15.07.2001, p. 787-796.

Research output: Contribution to journalArticle

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