Shang Xiaoyun, Wang Li, Niu Wei, Meng Gang, Fu Xiaolan, Ni Bing, Lin Zhihua, Yang Zhao, Chen Xiaolin, Wu Yuzhang
Institute of Immunology PLA, Third Military Medical University, Shapingba, Chongqing, P. R. China.
Eur J Immunol. 2009 Aug;39(8):2248-58. doi: 10.1002/eji.200939338.
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.
对肽 - MHC复合物与TCR亲和力增加的改变肽配体为癌症免疫疗法提供了一种替代天然T细胞表位的策略，因为它们可以募集并刺激更强的T细胞库。然而，尚不清楚TCR接触残基的改变如何改善肽 - MHC复合物与TCR分子之间的相互作用。在本研究中，我们引入了一种分子模拟策略，通过替换潜在的TCR接触残基来优化肿瘤免疫显性表位NY - ESO - 1(157 - 165)。我们将分子模拟与T细胞激活能力测定相关联，并检测TCR接触残基修饰对T细胞识别的影响。鉴定出一种激动剂肽W5F，其在Trp5处被Phe取代，并且它表现出更强的能力来诱导与野生型肽的交叉反应性CTL反应。此外，W5F诱导的CTL可以与野生型肽一起维持，并且在裂解天然表达NY - ESO - 1的肿瘤细胞方面具有更高的能力。这些结果为通过在TCR接触位点进行取代来增强表位的免疫原性提供了重要见解，并揭示了一种用于合理治疗性肽疫苗设计的新型分子模拟方法。
