The use of reverse immunology to identify HLA-A2 binding epitopes in Tie-2

• Published in: Cancer Immunology, Immunotherapy Vol. 55; no. 8; pp. 1004 - 1010
• Main Authors: RAMAGE, Judith M, SPENDLOVE, Ian, REES, Robert, MOSS, Robert S, DURRANT, Lindy G
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-08-2006; Springer Nature B.V; Springer-Verlag
• Subjects: Algorithms; Amino acids; Animals; Antigens; Antigens, Neoplasm - immunology; Antineoplastic agents; Base Sequence; Binding Sites; Biological and medical sciences; Cancer vaccines; Cytotoxicity; Endothelium; Epitopes, T-Lymphocyte - immunology; HLA-A2 Antigen - metabolism; Immunologic Techniques; Immunology; Immunotherapy; Lymphocytes; Medical sciences; Mice; Mice, Transgenic; Molecular Sequence Data; Peptides; Pharmacology. Drug treatments; Receptor, TIE-2 - immunology; Symposium Paper; T-Lymphocytes, Cytotoxic - immunology; Tumors; United Kingdom > UK; Modification; HLA-System; Antigenic determinant; Major histocompatibility system; Rodentia; Transgenic mice; Transgenic animal; Tie2 receptor; Vertebrata; Mammalia; Immunology; Treatment; HLA-A-Locus; Mouse; Immunotherapy; HLA-A0201; Reverse immunology; Anchor modifications; Cytotoxic T lymphocyte; Class I histocompatibility antigen; Cytotoxic T lymphocytes
• ISSN: 0340-7004; 1432-0851; 1365-2567
• DOI: 10.1007/s00262-005-0119-1

A potential target for a cancer vaccine would be receptors, such as Tie-2 which are over expressed on tumour endothelium. Using computer aided motif predictions for possible HLA class I epitopes, we have identified peptides from Tie-2 that should bind with a range of affinities to HLA-A*0201. No direct correlation between predicted values and actual binding affinities was observed. Although, the programs did produce a number of false positives, two epitopes were predicted that bound with relatively high affinity when compared with an influenza peptide. We have previously identified a Tie-2 epitope and shown that it was only immunogenic when we substituted preferred amino acids at key anchor residues to increase binding affinity. In this study we used a similar approach to generate modified epitopes. When HLA-A2 transgenic mice were immunised with peptides, CTL killing of the target cells was only achieved when the wild type epitope was presented at moderate levels. Moreover, the efficiency of immunisation was increased when we linked CD4 epitopes to CD8 epitopes. Caution should therefore be employed in the use of both reverse immunology and anchor modification of CTL epitopes in the identification of CTL epitopes for cancer vaccines.