Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues
Xiaoyun Shang1, Li Wang, Wei Niu
1Institute of Immunology PLA, Third Military Medical University, Shapingba, Chongqing, P. R. China.
Abstract:
Altered peptide ligands with increased affinity of the peptide-MHC complex for the TCR provide an alternative strategy to natural T-cell epitopes for cancer immunotherapy, as they can recruit and stimulate stronger T-cell repertoires. However, it remains unclear how alterations of the TCR contact residues improve the interaction between the peptide-MHC complex and the TCR molecule. In this study, we introduced a molecular simulation strategy to optimize a tumor immunodominant epitope NY-ESO-1(157-165) by the substitution of the potential TCR contact residues. We correlated molecule simulation with T-cell activation capacity assay and detected the effect of modifications of TCR contact residues on T-cell recognition. An agonist peptide W5F with substitution at Trp5 with Phe was identified and it exhibits a stronger ability to induce a cross-reactive CTL response with the WT peptide. Additionally, the W5F-induced CTL could be maintained with the WT peptide and possess higher capacity in lysing native NY-ESO-1-expressing tumor cells. These results provide important insights into the enhanced immunogenicity of epitopes through substitution at the TCR contact sites and revealed a novel molecular simulation approach for rational therapeutic peptide vaccine design.
Insights
Optimizing cancer immunotherapies, researchers modified a tumor epitope to enhance T-cell responses. A new peptide, W5F, demonstrated superior tumor cell killing, offering a promising approach for therapeutic peptide vaccine design.
Area of Science:
- Immunology
- Computational Biology
- Oncology
Background:
- Altered peptide ligands (APLs) enhance cancer immunotherapy by increasing peptide-MHC affinity for T-cell receptors (TCRs).
- The precise mechanisms by which TCR contact residue modifications improve peptide-MHC-TCR interactions remain incompletely understood.
Purpose of the Study:
- To investigate how altering TCR contact residues in a tumor epitope impacts T-cell recognition and activation.
- To develop a molecular simulation strategy for optimizing epitopes for cancer immunotherapy.
Main Methods:
- Employed molecular simulation to optimize the NY-ESO-1(157-165) epitope by substituting potential TCR contact residues.
- Correlated simulation data with T-cell activation assays to assess the impact of modifications on T-cell recognition.
Main Results:
- Identified an agonist peptide, W5F, with a Trp5 to Phe substitution, exhibiting enhanced induction of cross-reactive cytotoxic T lymphocyte (CTL) responses against the wild-type (WT) peptide.
- W5F-induced CTLs demonstrated sustained activity and improved lysis of NY-ESO-1-expressing tumor cells.
Conclusions:
- Epitope modification at TCR contact sites can significantly enhance immunogenicity.
- A novel molecular simulation approach facilitates rational design of therapeutic peptide vaccines for cancer immunotherapy.
