A modified HLA-A0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses
A modified HLA-A0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses
复制标题
来自人类癌蛋白 (hPEBP4) 的修饰的 HLA-A0201 限制性 CTL 表位可诱导更有效的抗肿瘤反应
DOI：
10.1038/cmi.2017.155
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发表时间：
2018
影响因子：
24.1
通讯作者：
Li Nan
中科院分区：
文献类型：
--
作者：
Sun Weihong;Shi Junyi;Wu Jian;Zhang Junchu;Chen Huabiao;Li Yuanyuan;Liu Shuxun;Wu Yanfeng;Tian Zhigang;Cao Xuetao;Li Nan
我们先前发现人磷脂酰乙醇胺结合蛋白4(HPEBP4)是一种抗细胞凋亡蛋白，在乳腺癌细胞、卵巢癌细胞和前列腺癌细胞中表达增加，但在正常组织中表达水平较低，这使得hPEBP4成为免疫治疗的一个有吸引力的靶点。在这里，我们开发了hPEBP4来源的免疫原肽来诱导针对乳腺癌的抗原特异性细胞毒性T淋巴细胞(CTL)。用多肽-MHC结合算法预测了一组hPEBP4衍生多肽，以表征它们与人类白细胞抗原A2.1的亲和力和免疫原性。我们发现了一种新的免疫原肽P40-48(TLFCQGLEV)，它能够在人类白细胞抗原A2.1/Kb转基因小鼠以及乳腺癌患者的外周血淋巴细胞中诱导特异性CTL反应。此外，P40-48序列中的氨基酸取代提高了其对自身抗原hPEBP4的免疫原性，从而规避了耐受性。我们通过首选辅助的HLA-A*0201锚基替换来设计多肽类似物，它诱导与天然多肽发生交叉反应的CTL。有几个类似物能够稳定地与HLA-A*0201结合，并比天然序列更好地诱导特异性CTL反应。重要的是，通过接种两种类似物诱导的CTL过继转移比天然多肽更有效地抑制肿瘤生长。这些数据表明，具有高免疫原性的多肽类似物有望成为多肽介导的治疗性癌症疫苗的候选对象。
We previously identified human phosphatidylethanolamine-binding protein 4 (hPEBP4) as an antiapoptotic protein with increased expression levels in breast, ovarian and prostate cancer cells, but low expression levels in normal tissues, which makes hPEBP4 an attractive target for immunotherapy. Here, we developed hPEBP4-derived immunogenic peptides for inducing antigen-specific cytotoxic T lymphocytes (CTLs) targeting breast cancer. A panel of hPEBP4-derived peptides predicted by peptide-MHC-binding algorithms was evaluated to characterize their HLA-A2.1 affinity and immunogenicity. We identified a novel immunogenic peptide, P40–48 (TLFCQGLEV), that was capable of eliciting specific CTL responses in HLA-A2.1/Kbtransgenic mice, as well as in peripheral blood lymphocytes from breast cancer patients. Furthermore, amino-acid substitutions in the P40–48 sequence improved its immunogenicity against hPEBP4, a self-antigen, thus circumventing tolerance. We designed peptide analogs by preferred auxiliary HLA-A*0201 anchor residue replacement, which induced CTLs that were crossreactive to the native peptide. Several analogs were able to stably bind to HLA-A*0201 and elicit specific CTL responses better than the native sequence. Importantly, adoptive transfer of CTLs induced by vaccination with two analogs more effectively inhibited tumor growth than the native peptide. These data indicate that peptide analogs with high immunogenicity represent promising candidates for peptide-mediated therapeutic cancer vaccines.