Peptides derived from human insulin-like growth factor (IGF)-II mRNA binding protein 3 can induce human leukocyte antigen-A2-restricted cytotoxic T lymphocytes reactive to cancer cells
Peptides derived from human insulin-like growth factor (IGF)-II mRNA binding protein 3 can induce human leukocyte antigen-A2-restricted cytotoxic T lymphocytes reactive to cancer cells
复制标题
源自人胰岛素样生长因子 (IGF)-II mRNA 结合蛋白 3 的肽可诱导人白细胞抗原 A2 限制性细胞毒性 T 淋巴细胞对癌细胞产生反应
DOI：
10.1111/j.1349-7006.2010.01780.x
复制
发表时间：
2011
期刊：
影响因子：
5.7
通讯作者：
et al.
中科院分区：
文献类型：
--
作者：
Y. Tomita;et al.
胰岛素样生长因子II mRNA结合蛋白3（IMP-3）是一种癌胚蛋白，在包括肺癌在内的各种恶性肿瘤中表达。本研究旨在鉴定来自IMP-3的免疫原性肽，这些肽可诱导肿瘤反应性和人类白细胞抗原（HLA）-A2（A*02：01）限制性细胞毒性T淋巴细胞（CTL）用于肺癌免疫治疗。分析了40种预测与HLA-A2结合的人IMP-3衍生肽，以确定其在HLA-A2. 1（HHD）转基因小鼠（Tgm）中诱导HLA-A2限制性T细胞的能力。我们发现三种IMP-3肽在HLA-A2. 1 Tgm中引发HLA-A2-限制性CTL。其中，从HLA-A2-阳性健康供体和肺癌患者中可重复建立对IMP-3515 NLSSAEVVV 523具有反应性的人CTL细胞系。另一方面，IMP-3199 RLLVPTQFV 207可重复诱导健康供体的IMP-3特异性和HLA-A2限制性CTL，但在HLA-A2. 1 Tgm中不致敏CTL。重要的是，从健康供体和癌症患者中产生的这两种IMP-3肽特异性CTL有效地杀死了天然表达IMP-3和HLA-A2的癌细胞。抗HLA I类和抗HLA A2单克隆抗体可显著抑制细胞毒性，但抗HLA II类单克隆抗体未抑制细胞毒性。此外，通过肽诱导的CTL特异性杀伤HLA-A2阳性IMP-3转染子而非亲本IMP阴性细胞系，证实了源自IMP-3蛋白的这两个表位的天然加工。这表明这两种IMP-3衍生肽代表了高度免疫原性的CTL表位，可能是肺癌免疫治疗的有吸引力的靶点。（Cancer Sci2011; 102：71-80）
Insulin‐like growth factor‐II mRNA binding protein 3 (IMP‐3) is an oncofetal protein expressed in various malignancies including lung cancer. This study aimed to identify immunogenic peptides derived from IMP‐3 that can induce tumor‐reactive and human leukocyte antigen (HLA)‐A2 (A*02:01)‐restricted cytotoxic T lymphocytes (CTL) for lung cancer immunotherapy. Forty human IMP‐3‐derived peptides predicted to bind to HLA‐A2 were analyzed to determine their capacity to induce HLA‐A2‐restricted T cells in HLA‐A2.1 (HHD) transgenic mice (Tgm). We found that three IMP‐3 peptides primed HLA‐A2‐restricted CTL in the HLA‐A2.1 Tgm. Among them, human CTL lines reactive to IMP‐3515NLSSAEVVV523were reproducibly established from HLA‐A2‐positive healthy donors and lung cancer patients. On the other hand, IMP‐3199RLLVPTQFV207reproducibly induced IMP‐3‐specific and HLA‐A2‐restricted CTL from healthy donors, but did not sensitize CTL in the HLA‐A2.1 Tgm. Importantly, these two IMP‐3 peptide‐specific CTL generated from healthy donors and cancer patients effectively killed the cancer cells naturally expressing both IMP‐3 and HLA‐A2. Cytotoxicity was significantly inhibited by anti‐HLA class I and anti‐HLA‐A2 monoclonal antibodies, but not by the anti‐HLA‐class II monoclonal antibody. In addition, natural processing of these two epitopes derived from the IMP‐3 protein was confirmed by specific killing of HLA‐A2‐positive IMP‐3‐transfectants but not the parental IMP‐negative cell line by peptide‐induced CTL. This suggests that these two IMP‐3‐derived peptides represent highly immunogenic CTL epitopes that may be attractive targets for lung cancer immunotherapy. (Cancer Sci2011; 102: 71–80)