Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy
Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy
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DOI：
10.1111/j.1349-7006.2007.00603.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.7
通讯作者：
Tahara, Hideaki
中科院分区：
文献类型：
--
作者：
Suda, Takako;Tsunoda, Takuya;Tahara, Hideaki
为了开发癌症疫苗疗法，我们已经搜索了可能的表位肽，其可以引发针对TTK蛋白激酶（TTK）、淋巴细胞抗原6复合位点K（LY 6 K）和胰岛素样生长因子（IGF）-II mRNA结合蛋白3（IMP-3）的细胞毒性T淋巴细胞（CTL），这些蛋白在先前被鉴定为在大多数肺癌和食管癌中被反式激活。我们分别筛选了31、17和17个与TTK、LY 6 K和IMP-3部分结合的候选人类白细胞抗原（HLA）-A*2402结合肽。结果，我们成功地建立了由TTK-567（SYRNEIAYL）、LY 6 K-177（RYCNLEGPPI）和IMP-3-508（KTVNELQNL）刺激的强CTL克隆，其对用候选肽脉冲的HLA-A24阳性靶细胞具有特异性细胞毒性活性。随后对CTL克隆的分析也揭示了它们对内源性表达TTK、LY 6 K或IMP-3的肺和食管肿瘤细胞的细胞毒性活性。冷靶抑制测定进一步证实CTL细胞克隆特异性识别MHC I类-肽复合物。我们的结果强烈暗示TTK、LY 6 K和IMP-3是CTL识别的新的肿瘤相关抗原，并且TTK-567（SYRNEIAYL）、LY 6 K-177（RYCNLEGPPI）和IMP-3-508（KTVNELQNL）是HLA-A24限制性表位肽，其可以诱导针对表达TTK、LY 6 K和IMP-3的肺癌和食管癌细胞的有效和特异性免疫应答。
For the development of cancer vaccine therapies, we have searched for possible epitope peptides that can elicit cytotoxic T lymphocytes (CTL) to the TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K) and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3), which were previously identified to be transactivated in the majority of lung and esophageal cancers. We screened 31, 17 and 17 candidate human leukocyte antigen (HLA)-A*2402-binding peptides to parts of TTK, LY6K and IMP-3, respectively. As a result, we successfully established strong CTL clones stimulated by TTK-567 (SYRNEIAYL), LY6K-177 (RYCNLEGPPI) and IMP-3-508 (KTVNELQNL) that have specific cytotoxic activities against the HLA-A24-positive target cells pulsed with the candidate peptides. Subsequent analysis of the CTL clones also revealed their cytotoxic activities against lung and esophageal tumor cells that endogenously express TTK, LY6K or IMP-3. A cold target inhibition assay further confirmed that the CTL cell clones specifically recognized the MHC class I-peptide complex. Our results strongly imply that TTK, LY6K and IMP-3 are novel tumor-associated antigens recognized by CTL, and TTK-567 (SYRNEIAYL), LY6K-177 (RYCNLEGPPI) and IMP-3-508 (KTVNELQNL) are HLA-A24-restricted epitope peptides that can induce potent and specific immune responses against lung and esophageal cancer cells expressing TTK, LY6K and IMP-3.