Ran, a small GTPase gene, encodes cytotoxic T lymphocyte (CTL) epitopes capable of inducing HLA-A33-restricted and tumor-reactive CTLs in cancer patients
Ran, a small GTPase gene, encodes cytotoxic T lymphocyte (CTL) epitopes capable of inducing HLA-A33-restricted and tumor-reactive CTLs in cancer patients
复制标题
DOI：
10.1158/1078-0432.ccr-04-0818
复制
发表时间：
2004-10-01
影响因子：
11.5
通讯作者：
Itoh, K
中科院分区：
文献类型：
--
作者：
Azuma, K;Sasada, T;Itoh, K
目的：鉴定一种能够以限制HLA-A33的方式诱导ctl对肿瘤细胞产生反应的肿瘤相关抗原和肽编码基因，为HLA-A33（+）肿瘤患者的特异性免疫治疗提供科学依据。实验设计：采用表达基因克隆法鉴定肿瘤相关抗原基因。采用Northern blot和免疫组化分别检测各组细胞和组织中mRNA和蛋白的表达水平。研究人员检测了合成肽在癌症患者外周血单个核细胞中诱导HLA-A33（+）肿瘤反应性ctl的能力。结果：小GTPase基因Ran通过调控核胞质运输、有丝分裂纺锤体组织和核膜形成来控制细胞周期，该基因编码的表位可被浸润到胃腺癌的T细胞建立的hla - a33限制性ctl识别。在大多数癌细胞系和癌组织中，Ran基因在mRNA和蛋白水平上的表达均增加。然而，在周围的正常细胞或组织中没有增强。就测试而言，在正常组织中也检测不到。位置48-56和87-95的随机衍生肽可以诱导CD8（+）肽特异性ctl以HLA- i类限制的方式对HLA- a33（+）上皮癌患者的肿瘤细胞产生反应。结论：由于其在癌细胞中的表达增加，参与恶性转化和/或癌细胞的增殖，这两种ran定向肽可能是针对HLA-A33（+）上皮癌的特异性免疫治疗的有力候选者。
Purpose: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33-restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33(+) cancer patients.Experimental Design: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33(+) tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients.Result: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33-restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48-56 and 87-95 could induce CD8(+) peptide-specific CTLs reactive to tumor cells from HLA-A33(+) epithelial cancer patients in a HLA class I-restricted manner.Conclusions: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33(+) epithelial cancers.