title: Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues.
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.
authors: Institute of Immunology PLA, Third Military Medical University, Shapingba, Chongqing, P. R. China.
authors: Xiaoyun
authors: X
authors: Shang
authors: Li
authors: L
authors: Wang
authors: Wei
authors: W
authors: Niu
authors: Gang
authors: G
authors: Meng
authors: Xiaolan
authors: X
authors: Fu
authors: Bing
authors: B
authors: Ni
authors: Zhihua
authors: Z
authors: Lin
authors: Zhao
authors: Z
authors: Yang
authors: Xiaolin
authors: X
authors: Chen
authors: Yuzhang
authors: Y
authors: Wu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D045744:Cell Line, Tumor; D003198:Computer Simulation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma