Rational optimization of tumor epitopes using in silico analysis-assisted substitution of TCR contact residues
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 peptideMHC complex and the TCR molecule. In this study, we introduced a molecular simulation strategy to optimize a tumor immunodominant epitope NY-ESO-1 157165 by the substitution of the potential TCR contact residues. We correlated molecule simulation with Tcell activation capacity assay and detected the effect of modifications of TCR contact residues on Tcell recognition. An agonist peptide W5F with substitution at Trp5 with Phe was identified and it exhibits a stronger ability to induce a crossreactive 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-ex pressing 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.
Xiaoyun Shang Yuzhang Wu Li Wang Wei Niu Gang Meng Xiaolan Fu Bing Ni Zhihua Lin Zhao Yang Xiaolin Chen
Institute of Immunology PLA, Third Military Medical University, Shapingba, Chongqing, P.R.China Department of Pathology, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing College of Chemical and Bioengineering, Chongqing Institute of Technology, Yangjiaping, Chongqing, P
国际会议
武汉
英文
269-279
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）