HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy
HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy
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DOI：
10.1593/neo.08576
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Yang, Shi-Ming
中科院分区：
文献类型：
--
作者：
Chen, Ting;Tang, Xu-Dong;Yang, Shi-Ming
用于癌症免疫治疗的肽疫苗接种需要鉴定源自与肿瘤相关的抗原蛋白的肽表位。乙酰肝素酶（Hpa）在多种晚期肿瘤中广泛表达，是一种新的肿瘤相关抗原。本研究旨在预测和鉴定人Hpa蛋白中HLA-A2限制性细胞毒性T淋巴细胞（CTL）抗原表位。为此目的，使用以下四步程序鉴定HLA-A2限制性CTL表位：1）从人Hpa的氨基酸序列进行基于计算机的表位预测，2）肽结合测定以确定预测的蛋白质与HLA-A2分子的亲和力，3）体外刺激针对预测的肽的初级T细胞应答，以及4）测试针对表达Hpa抗原和/或HLA-A2的不同种类的癌细胞的诱导的CTL。结果表明，在测试的肽中，由含有残基525-533（PAFSYSFFV，Hpa 525）、277-285（KMLKSFLKA，Hpa 277）和405-413（WLSLLFKKL，Hpa 405）的人Hpa的肽诱导的效应物可以有效地裂解Hpa阳性和HLA-A2匹配的各种肿瘤细胞系。我们还发现，这些肽特异性CTL不能裂解低Hpa活性的自体淋巴细胞。进一步的研究显示，与阴性肽相比，Hpa 525、Hpa 277和Hpa 405肽增加了产生IFN-γ的T细胞的频率。我们的研究结果表明，Hpa 525，Hpa 277和Hpa 405肽是新的HLA-A2限制性CTL表位，能够在体外诱导Hpa特异性CTL。由于Hpa在大多数晚期恶性肿瘤中表达，因此基于Hpa 525、Hpa 277和Hpa 405肽的疫苗可用于晚期肿瘤患者的免疫治疗。
Peptide vaccination for cancer immunotherapy requires identification of peptide epitopes derived from antigenic proteins associated with tumors. Heparanase (Hpa) is broadly expressed in various advanced tumors and seems to be an attractive new tumor-associated antigen. The present study was designed to predict and identify HLA-A2-restricted cytotoxic T lymphocyte (CTL) epitopes in the protein of human Hpa. For this purpose, HLA-A2-restricted CTL epitopes were identified using the following four-step procedure: 1) a computer-based epitope prediction from the amino acid sequence of human Hpa, 2) a peptide-binding assay to determine the affinity of the predicted protein with the HLA-A2 molecule, 3) stimulation of the primary T-cell response against the predicted peptides in vitro, and 4) testing of the induced CTLs toward different kinds of carcinoma cells expressing Hpa antigens and/or HLA-A2. The results demonstrated that, of the tested peptides, effectors induced by peptides of human Hpa containing residues 525-533 (PAFSYSFFV, Hpa525), 277-285 (KMLKSFLKA, Hpa277), and 405-413 (WLSLLFKKL, Hpa405) could effectively lyse various tumor cell lines that were Hpa-positive and HLA-A2-matched. We also found that these peptide-specific CTLs could not lyse autologous lymphocytes with low Hpa activity. Further study revealed that Hpa525, Hpa277, and Hpa405 peptides increased the frequency of IFN-gamma-producing T cells compared to a negative peptide. Our results suggest that Hpa525, Hpa277, and Hpa405 peptides are new HLA-A2-restricted CTL epitopes capable of inducing Hpa-specific CTLs in vitro. Because Hpa is expressed in most advanced malignant tumors, Hpa525, Hpa277, and Hpa405 peptide-based vaccines may be useful for the immunotherapy for patients with advanced tumors.