T细胞受体识别肿瘤多肽疫苗的结构和功能研究

One of the main function of T cell is the surveillance of unhealthy cells through our bodies with the recognition of targets by the T cell receptor(TCR). How to manipulate T cell recognition to treat diseases such as cancer is one of the most exciting area. One approach is to use peptide vaccine to stimulate the endogenous T cells to attack tumor cells. However one limitation of this cancer immunotherapy is that peptide vaccines usually can not evoke immune response strongly enough. We investigated a set of peptide variants which ordered a magnitude more effective in vaccines in a mouse colon tumor model than the wildtype peptide from the tumor antigen. These peptide variants will form complexes with the relevant mouse MHCI molecule, Ld, and be recognized by tumor specific TCR. The preliminary data of the binding kinetic by the TCR indicates that the effective peptide variant can enhance the recognition. We also got the preliminary data of the low resolution structure of Ld/wildtype peptide complexe. We would like to keep forward to solve the high resolution structure of several important Ld/peptide vaccines. Also We would like to understand the mechanism of how peptide vaccines can be more effective to treat the cancer and help to design more effective peptide vaccine based on it.

T细胞主要的功能之一就是通过TCR（T细胞受体）识别体内异常细胞,进行免疫监视和防御。如何去操控T细胞识别并去治疗包括癌症在内的疾病是现在的热点问题之一。一个策略就是用多肽疫苗激活体内T细胞去攻击肿瘤细胞。然而此免疫疗法的一个瓶颈就是引发的免疫应答强度往往不够。我们选取一组有抗小鼠结肠癌活性的模拟多肽疫苗作为研究对象。这些多肽和小鼠的MHC（主要组织相容性复合体）I类分子中的Ld分子结合后被肿瘤特异性TCR识别从而激活T细胞。我们初步的分子相互识别实验提示，高效的模拟多肽疫苗能被肿瘤特异性TCR更好识别，从而加强了免疫识别和应答。初步的低分辨Ld/多肽结构数据也为随后高分辨率的多肽疫苗结构研究打下了良好的基础。我们将继续研究多肽疫苗被识别的动力学过程和解析高分辨率的Ld/多肽复合物的三维结构，并提出模拟多肽疫苗优化的相关理论和法则。

T细胞可以很强的识别抗原多肽并杀伤肿瘤细胞，然而肿瘤自身产生的母体多肽所激活的免疫强度往往较弱，因此当前如何操控T细胞的特异性来有效杀伤肿瘤细胞已经成为国际免疫医学的研究热点。在一年期基金资助下，我们选取小鼠结肠癌作为模型，研究高效多肽疫苗相较于肿瘤母体多肽使小鼠存活率从0提升为100%的分子机制和结构基础，现已顺利完成预期目标。研究发现肿瘤母体多肽发生改变后，能和T细胞受体以更高亲和力结合，从而更好地激活了T细胞。目前我们已分别获得了高效多肽疫苗和母体多肽疫苗与MHC的复合物2.6埃高分辨率三维结构。我们也进行了TCR与多肽疫苗及其多个突变体的识别动力学分析来解释这一现象，提出了基于识别优化的疫苗设计新思路。这些工作将为模拟多肽疫苗的优化提供理论依据,指导设计新的肿瘤多肽疫苗，多篇文章正在投稿或写作中。