Houghton Colin S B, Engelhorn Manuel E, Liu Cailan, Song Da, Gregor Polly, Livingston Phillip O, Orlandi Francesca, Wolchok Jedd D, McCracken James, Houghton Alan N, Guevara-Patiño José A
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, United States.
Vaccine. 2007 Jul 20;25(29):5330-42. doi: 10.1016/j.vaccine.2007.05.008. Epub 2007 Jun 4.
One strategy to generate T-cell responses to tumors is to alter subdominant epitopes through substitution of amino acids that are optimal anchors for specific MHC molecules, termed heteroclitic epitopes. This approach is manually error-prone and time-consuming. In here, we describe a computer-based algorithm (EpitOptimizer) for the streamlined design of heteroclitic epitopes. Analysis of two cancer-related proteins showed that EpitOptimizer-generated peptides have enhanced MHC-I binding compared with their wild-type counterparts; and were able to induce stronger CD8+ T-cell responses against their native epitope. These data demonstrate that this approach can serve as the basis of epitope-engineering against cancer and intracellular pathogens.
一种产生针对肿瘤的T细胞反应的策略是通过替换作为特定MHC分子最佳锚定残基的氨基酸来改变亚优势表位，即所谓的异源性表位。这种方法容易出现人工错误且耗时。在此，我们描述了一种基于计算机的算法（表位优化器），用于简化异源性表位的设计。对两种癌症相关蛋白的分析表明，与野生型对应物相比，表位优化器生成的肽具有增强的MHC-I结合能力；并且能够诱导针对其天然表位的更强的CD8+ T细胞反应。这些数据表明，这种方法可作为针对癌症和细胞内病原体的表位工程的基础。
