The immunogenicity of a novel cytotoxic T lymphocyte epitope from tumor antigen PL2L60 could be enhanced by 4-chlorophenylalanine substitution at position 1
The immunogenicity of a novel cytotoxic T lymphocyte epitope from tumor antigen PL2L60 could be enhanced by 4-chlorophenylalanine substitution at position 1
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肿瘤抗原 PL2L60 的新型细胞毒性 T 淋巴细胞表位的免疫原性可以通过位置 1 的 4-氯苯丙氨酸取代来增强
DOI：
10.1007/s00262-013-1478-7
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发表时间：
2013-11-01
影响因子：
5.8
通讯作者：
Gao, Yan-feng
中科院分区：
文献类型：
--
作者：
Shi, Ran-ran;Liu, Jing;Gao, Yan-feng
PIWIL 2是PIWI/AGO家族的成员，在生殖系干细胞和癌前干细胞中表达，而在成体细胞中不表达。PIWIL 2在肿瘤发生中起重要作用。它被认为是癌症-睾丸抗原（CT 80）。据报道，PIWIL 2的剪接片段PL 2L 60在癌细胞系中广泛表达。在这项研究中，来自PL 2L 60的HLA-A2限制性表位通过在线工具进行预测。为了提高天然表位的活性，选择具有强结合亲和力的候选肽P281来研究修饰策略。引入一系列芳香族氨基酸取代P281的第一个残基。然后，我们测试了肽类似物的结合亲和力和稳定性以及它们在体外和体内引发特异性免疫应答的能力。结果表明，[4-Cl-Phe（1）]P281诱导的细胞毒性T淋巴细胞（CTL）活性比P281及其类似物更强。由该类似物诱导的CTL能够以HLA-A2限制性和抗原特异性的方式裂解靶细胞。[4-Cl-Phe（1）]P281在人血清中也表现出最好的抗降解性。总之，在第一位引入非天然氨基酸4-Cl-Phe可以增强天然表位诱导细胞毒性T淋巴细胞的活性。这可能是一个很好的策略，修改其他有前途的天然表位。本研究中鉴定的新表位可用作HLA-A2阳性的表达PL 2L 60的肿瘤患者的免疫治疗的新候选物。
PIWIL2, a member of PIWI/AGO family, is expressed in germline stem cells and precancerous stem cells, but not in adult somatic cells. PIWIL2 plays an important role in tumor development. It is considered as a cancer-testis antigen (CT80). It has been reported that the spliced fragment of PIWIL2, PL2L60, was widely expressed in cancer cell lines. In this study, HLA-A2-restricted epitopes from PL2L60 were predicted by online tools. To improve the activity of the native epitope, a candidate peptide P281 with potent binding affinity was chosen to investigate the modification strategy. A series of aromatic amino acids were introduced to substitute the first residue of P281. Then, we tested the binding affinity and stability of the peptide analogs and their ability to elicit specific immune responses both in vitro and in vivo. Our results indicated that the cytotoxic T lymphocytes (CTLs) induced by [4-Cl-Phe(1)]P281 could elicit more potent activities than that of P281 and other analogs. The CTLs induced by this analog could lyze target cells in HLA-A2-restricted and antigen-specific manners. [4-Cl-Phe(1)]P281 also showed the best resistance against degradation in human serum. In conclusion, the introduction of the unnatural amino acid, 4-Cl-Phe, into the first position could enhance the activity of the native epitope to induce cytotoxic T lymphocytes. It might be a good strategy to modify other promising native epitopes. The novel epitopes identified in this study could be used as novel candidates to the immunotherapy of HLA-A2 positive patients with tumors expressing PL2L60.