Azuma Koichi, Sasada Tetsuro, Takedatsu Hiroko, Shomura Hiroki, Koga Makoto, Maeda Yoshiaki, Yao Akihisa, Hirai Tatsuya, Takabayashi Arimichi, Shichijo Shigeki, Itoh Kyogo
Department of Immunology and Research Center of Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science, Kurume University School of Medicine, Kurume, Japan.
Clin Cancer Res. 2004 Oct 1;10(19):6695-702. doi: 10.1158/1078-0432.CCR-04-0818.
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.
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.
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.
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.
鉴定编码肿瘤相关抗原和肽的基因，该肽能够诱导以HLA - A33限制方式对肿瘤细胞产生反应的细胞毒性T淋巴细胞（CTL），为HLA - A33 +癌症患者的特异性免疫治疗提供科学依据。
采用表达基因克隆方法鉴定肿瘤相关抗原基因。分别用Northern印迹分析和免疫组织化学检测各种细胞和组织中的mRNA和蛋白质表达水平。检测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。
发现一种小GTP酶Ran基因，它通过调节核质运输、有丝分裂纺锤体组织和核膜形成来控制细胞周期，该基因编码从浸润胃腺癌的T细胞建立的HLA - A33限制的CTL所识别的表位。Ran基因在大多数癌细胞系和癌组织中的mRNA和蛋白质水平均升高。然而，在周围正常细胞或组织中未增强。在所检测的正常组织中也未检测到。48 - 56位和87 - 95位的Ran衍生肽能够以HLA I类限制方式诱导对HLA - A33 +上皮癌患者的肿瘤细胞产生反应的CD8 +肽特异性CTL。
由于其在癌细胞中的表达增加，并参与恶性转化和/或癌细胞的增殖增强，这两种Ran导向的肽可能是用于针对HLA - A33 +上皮癌进行特异性免疫治疗的有力候选物。
