Identification and design of p53-derived HLA-A2-binding peptides with increased CTL immunogenicity

Citation
Tr. Petersen et al., Identification and design of p53-derived HLA-A2-binding peptides with increased CTL immunogenicity, SC J IMMUN, 53(4), 2001, pp. 357-364
Citations number
47
Categorie Soggetti
Immunology
Journal title
SCANDINAVIAN JOURNAL OF IMMUNOLOGY
ISSN journal
03009475 → ACNP
Volume
53
Issue
4
Year of publication
2001
Pages
357 - 364
Database
ISI
SICI code
0300-9475(200104)53:4<357:IADOPH>2.0.ZU;2-M
Abstract
The replacement of a suboptimal amino acid in a primary anchor position wit h an optimal residue improves human leucocyte antigen (HLA) binding and imm unogenicity, while maintaining cytotoxic T lymphocyte (CTL) specificity. Us ing a neural network capable of performing quantitative predictions of pept ide binding to HLA-A2 molecules, we identified three p53 protein-derived no namer peptides with intermediate binding owing to suboptimal amino acids in the P2 anchor position. These peptides were synthesized along with the cor responding analogs, where the natural P2 residue had been replaced with the optimal leucine residue. All three modified peptides bound to and more eff iciently stabilized HLA-A2 molecules than the corresponding nonmodified pep tides. The HLA-A2 transgenic mice were used for immunization. Two of the ep itopes were more immunogenic in their modified than in their natural versio ns. The CTLs raised against the modified peptides efficiently killed the ta rget cells pulsed with the corresponding native peptide. In terms of sensit izing the targets cells for the CTL killing, the modified peptides were mor e efficient than native peptides. Finally, the CTLs induced by modified pep tide killed HLA-A2 transgenic mouse fibrosarcoma cells transfected with hum an p53 DNA. The data suggest that modified self-peptides derived from overe xpressed tumour-associated proteins can be used in vaccine development agai nst cancer, and that quantitative predictions of HLA binding is of value in the rational selection and improvement of target epitopes recognized by CT Ls.