Section for Cancer Immunotherapy, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Int J Oncol. 2011 Oct;39(4):1041-9. doi: 10.3892/ijo.2011.1089. Epub 2011 Jun 17.
Lengsin is an eye lens protein with a glutamine synthetase domain. We previously identified this protein as a lung carcinoma antigen through cDNA microarray analysis. Lengsin protein is overexpressed irrespective of the histological type of lung carcinoma, but not in normal tissues other than the lens. Therefore, to significantly extend the use of Lengsin-based T-cell immunotherapies for the treatment of patients with lung carcinoma, we searched for HLA-A0201-restricted epitopes from this protein by screening predicted Lengsin-derived candidate peptides for the induction of tumor-reactive CTLs. Four Lengsin-derived peptides were selected by computerized algorithm based on a permissive HLA-A0201 binding motif, and were used to immunize HLA-A0201 transgenic (HHD) mice. Two of the immunizing peptides, Lengsin(206-215)(FIYDFCIFGV) and Lengsin(270-279)(FLPEFGISSA), induced peptide-specific cytotoxic T lymphocytes (CTLs) in HHD mice, and thus were used to stimulate human peripheral blood lymphocytes in vitro. Lengsin(206-215) and Lengsin (270-279) also induced human peptide-specific CTLs, and we were able to generate Lengsin(206-215)- and Lengsin(270-279)-specific CTL clones. The Lengsin(270-279)-specific CTL clone specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A0201 and Lengsin, and HLA-A0201+/Lengsin+ lung carcinoma cells in an HLA-A0201-restricted manner. On the other hand, the Lengsin(206-215)-specific CTL clone failed to recognize HLA-A0201+/Lengsin+ target cells in the absence of cognate peptide. These results suggest that Lengsin(270-279) is naturally processed and presented by HLA-A0201 molecules on the surface of lung carcinoma cells and may be a new target for antigen-specific T-cell immunotherapy against lung cancer.
冷休克蛋白 LENGsin 是一种带有谷氨酰胺合成酶结构域的眼晶状体蛋白。我们先前通过 cDNA 微阵列分析，将该蛋白鉴定为肺癌相关抗原。无论肺癌的组织学类型如何，Lengsin 蛋白都过度表达，但在晶状体以外的正常组织中不表达。因此，为了显著扩大基于 Lengsin 的 T 细胞免疫疗法在治疗肺癌患者中的应用，我们通过筛选预测的 Lengsin 衍生候选肽来寻找该蛋白中与 HLA-A0201 限制表位，以诱导肿瘤反应性 CTL。根据允许的 HLA-A0201 结合基序，通过计算机算法选择了 4 种 Lengsin 衍生肽，并用于免疫 HLA-A0201 转基因（HHD）小鼠。两种免疫肽，Lengsin（206-215）（FIYDFCIFGV）和 Lengsin（270-279）（FLPEFGISSA），在 HHD 小鼠中诱导了肽特异性细胞毒性 T 淋巴细胞（CTL），因此用于体外刺激人外周血淋巴细胞。Lengsin（206-215）和 Lengsin（270-279）也诱导了人肽特异性 CTL，我们能够生成 Lengsin（206-215）和 Lengsin（270-279）特异性 CTL 克隆。Lengsin（270-279）特异性 CTL 克隆特异性识别肽脉冲 T2 细胞、表达 HLA-A0201 和 Lengsin 的 COS-7 细胞以及 HLA-A0201+/Lengsin+肺癌细胞，呈 HLA-A0201 限制方式。另一方面，在没有同源肽的情况下，Lengsin（206-215）特异性 CTL 克隆无法识别 HLA-A0201+/Lengsin+靶细胞。这些结果表明，Lengsin（270-279）可被肺癌细胞表面的 HLA-A0201 分子自然加工和呈递，可能成为针对肺癌的抗原特异性 T 细胞免疫治疗的新靶标。
