Amino acid modifications in the wild type sequence p53 232-240 overcome the poor immunogenicity of this self tumour epitope.
A major limitation in antigen-specific cancer vaccines is that most of the tumour antigens that are potent candidates for broad applicability originate from self proteins. The peptides presented by tumour cells are derived from tissue-specific differentiation proteins, from proteins altered by genetic mutation or by non mutated proteins that are normally silent in most adult tissues. As a consequence, T-cell responses elicited against those antigens are rather weak. Several data showed that amino acid modifications could enhance the immunogenicity of such antigens by priming T-cells that have escaped central tolerance based on a poor avidity. In this regard, this strategy could be powerful for inducing immunity against tumours. The present report focuses on the murine wild type epitope p53 232-240 that is poorly immunogenic. It shows that substitution of the two cysteine residues by serine or amino butyric acid derivatives and substitution of the two methionine residues by norleucine residues resulted in enhanced stability of the MHC/peptide complex. The MHC binding affinity of analogue peptides was enhanced between 10 and 100 fold. They were also potent immunogens, stronger than was the original wild type epitope; T-cell responses were increased up to 50 times. Moreover, the effector T-cells elicited by three of these peptides cross reacted with the natural epitope. These observations have important implications for strategies that use the modified-peptide epitope.
Baratin
Myriam
M
Immunologie des Pathologies Infectieuses et Tumorales, Département d'Immunologie, Institut Cochin, Labortoire associé no 9 du comité de Paris de la Ligue Nationale contre le Cancer, France.
Kayibanda
Michèle
M
Ziol
Marianne
M
Romieu
Raphäelle
R
Briand
Jean-Paul
JP
Guiller
Jean-Gérard
JG
Viguier
Mireille
M
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015202:Protein Engineering; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53