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Forced expression of the TNF-family gene in lung cancer cells produced therapeutic effects, stimulating antigen-presentation processes.

肺癌细胞中 TNF 家族基因的强制表达产生了治疗效果，刺激了抗原呈递过程。

基本信息

批准号：
12671337
负责人：
KOSHIKAWA Nobuko
金额：
$ 2.18万
依托单位：
Chiba Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671337/
关键词：
gene therapy CD40 ligand Fas ligand TNF-α lung cancer lung metastasis antigen presentaion dendritic cells 樹状細胞

项目摘要

Induction of cytotoxic T cells, responsible for cell-mediated immunity, requires the activation of dendritic cells (DC) which play a crucial role in antigen-presentation. We examined in this study whether activation of DC could be performed by gene transfer of the TNF-family gene and consequently antitumor effects were produced against lung cancer cells. Murine lung carcinoma Lewis cells were transfected with the TNF-family gene and established clones were subcutaneously inoculated into syngeneic mice. The growth of CD40 ligand-expressed tumors was significantly retarded compared with that of parent tumors and the number of spontaneous lung metastatic foci was significantly reduced. The immunocompetent mice that were inoculated with the Fas ligand-expressed tumors did not developed tumors and the mice generated tumor-specific protective immunity. The mice did not produce any lung metastatic foci. The growth of the TNF-α-expressed tumors was not different from that of parent tumors but the number of metastatic foci was significantly decreased. In order to analyze the involvement of DC in this antitumor effects, we cocultured DC that were obtained from bone-marrow cells with the transfected cells. DC formed cluster with Fas ligand-expressed but not parent tumors. The expression of CD86, an activation marker an costimulatory molecule of DC, was upregulated during the coculture with CD40 ligand-expressed tumors. Fas ligand and CD40 ligand seem to be involved in antigen processing and maturation of DC, respectively.

负责细胞介导免疫的细胞毒性T细胞的诱导需要在抗原呈递中起关键作用的树突状细胞（DC）的活化。在这项研究中，我们研究了是否可以通过转移TNF家族基因来激活DC，从而对肺癌细胞产生抗肿瘤作用。小鼠肺癌刘易斯细胞转染TNF家族基因，并建立克隆皮下接种到同基因小鼠。表达CD 40配体的肿瘤的生长与母瘤相比显著减慢，自发性肺转移灶的数量显著减少。接种Fas配体表达的肿瘤的免疫活性小鼠没有发生肿瘤，并且小鼠产生了肿瘤特异性保护性免疫。小鼠未产生任何肺转移灶。TNF-α表达的肿瘤的生长与母瘤的生长无差异，但转移灶的数量显著减少。为了分析DC在这种抗肿瘤作用中的参与，我们将从骨髓细胞中获得的DC与转染细胞共培养。DC与表达Fas配体的肿瘤成簇，但与母瘤不成簇。在与表达CD 40配体的肿瘤共培养期间，DC的活化标记物、共刺激分子CD 86的表达上调。Fas配体和CD 40配体可能分别参与DC的抗原加工和成熟。