Generation of cytotoxic T lymphocytes specific for native or modified peptides derived from the epidermal growth factor receptor pathway substrate 8 antigen
Generation of cytotoxic T lymphocytes specific for native or modified peptides derived from the epidermal growth factor receptor pathway substrate 8 antigen
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生成对源自表皮生长因子受体途径底物 8 抗原的天然或修饰肽具有特异性的细胞毒性 T 淋巴细胞
DOI：
10.1007/s00262-014-1631-y
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发表时间：
2015-02-01
影响因子：
5.8
通讯作者：
He, Yanjie
中科院分区：
文献类型：
--
作者：
Li, Yuhua;Zhou, Weijun;He, Yanjie
开发癌症免疫疗法的理想肿瘤抗原是一种仅在肿瘤细胞中表达的抗原。表皮生长因子受体途径底物8基因(Eps8)在多种肿瘤细胞中高表达，而在正常组织中不表达，可能是一种有效的肿瘤免疫治疗抗原。在这项研究中，对Eps8衍生的免疫疗法的潜在效用进行了体外和体内测试。使用三种基于计算机的算法设计了8个Eps8天然表位，这些表位与在中国人群中发现频率很高的HLA-A2.1分子具有潜在的高结合亲和力。在这8个多肽中，有3个与HLA-A2.1分子有中等亲和力的多肽被修饰在锚点残基上，以获得更强的免疫原性。这4个修饰多肽与T2细胞表面的HLAA2.1分子具有较强的亲和力和较低的解离率。在体外人PBMC和体内HLAA2.1/Kb转基因小鼠的功能测试中，每个天然和修饰的多肽启动的CTL都能分泌干扰素-γ，并以HLAA2.1限制性和EPS8特异性的方式对各种组织类型的癌细胞产生毒性。P101-109-2L和P276-284-1Y9V在体内外均优于其他修饰表位和天然表位。这些结果表明，在基于EPS8的免疫治疗中，对于HLA-A2.1阳性的癌症患者，使用本文确定的天然和修饰表位可能会对不同的肿瘤类型产生有效的抗癌免疫反应。
The ideal tumor antigen for the development of a cancer immunotherapy is one that is expressed only in tumor cells. The epidermal growth factor receptor pathway substrate 8 gene (Eps8) might be an effective antigen for cancer immunotherapy as it is overexpressed in a variety of cancer cells but not in normal tissues. In this study, the potential utility of an Eps8-derived immunotherapy was tested in vitro and in vivo. Three computer-based algorithms were used to design eight Eps8 native epitopes with potentially high binding affinity to the HLA-A2.1 molecule, which is found at a high frequency in the Chinese population. Of these eight, three peptides with a moderate affinity to the HLA-A2.1 molecule were modified at anchor residue positions to achieve stronger immunogenicity. These four modified peptides displayed stronger binding affinity to HLA-A2.1 molecules on T2 cells and a lower dissociation rate. In functional assays with human PBMCs in vitro and in HLA-A2.1/Kbtransgenic mice in vivo, CTLs primed by each native and modified peptide secreted IFN-γ and were toxic to cancer cells from a variety of tissue types in an HLA-A2.1-restricted and Eps8-specific manner. p101–109-2L and p276–284-1Y9V were superior to other modified and native epitopes both in vitro and in vivo. These results indicate that employing the native and modified epitopes identified here in Eps8-based immunotherapy for HLA-A2.1 positive cancer patients may result in efficient anticancer immune responses for diverse tumor types.