Amino acid modifications in the wild type sequence p53 232-240 overcome the poor immunogenicity of this self tumour
Myriam Baratin1, Michèle Kayibanda, Marianne Ziol
1Immunologie 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.
Abstract:
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.
Insights
Modifying self-protein cancer antigens, like p53, with amino acid changes significantly boosts their immunogenicity. These enhanced cancer vaccine peptides elicit stronger T-cell responses and could improve tumor immunity.
Area of Science:
- Immunology
- Cancer Research
- Vaccine Development
Background:
- Antigen-specific cancer vaccines face limitations due to weak T-cell responses against self-proteins.
- Tumor antigens derived from self-proteins often elicit weak T-cell immunity because T-cells are tolerant to them.
Purpose of the Study:
- To investigate if amino acid modifications can enhance the immunogenicity of the poorly immunogenic murine wild-type epitope p53 232-240.
- To assess the impact of these modifications on MHC/peptide stability, binding affinity, and T-cell responses.
Main Methods:
- The study focused on modifying cysteine and methionine residues within the p53 232-240 epitope.
- Amino acid substitutions included cysteine to serine or amino butyric acid derivatives, and methionine to norleucine.
- Assessed MHC/peptide complex stability, binding affinity, and T-cell responses to modified peptides.
Main Results:
- Modified peptides demonstrated enhanced stability of the MHC/peptide complex.
- MHC binding affinity increased 10-100 fold for analogue peptides compared to the wild-type epitope.
- T-cell responses were significantly increased (up to 50 times), with some modified peptides eliciting cross-reactive T-cells against the natural epitope.
Conclusions:
- Amino acid modifications can significantly enhance the immunogenicity of self-protein-derived tumor antigens.
- These modified peptides represent a promising strategy for developing more effective cancer vaccines.
- The enhanced immunogenicity and cross-reactivity have important implications for future cancer immunotherapy strategies.
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