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Potent antitumor immunotherapy mediated by IL-18 gene transfection to PAM212 cells

IL-18基因转染PAM212细胞介导的有效抗肿瘤免疫疗法

基本信息

批准号：
14571918
负责人：
IWANARI Shinnkiti
金额：
$ 2.56万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571918/
关键词：
IL-18 PAM212 Gene transfection ICE Antitumor effect INF-g oral SCC 癌遺伝子治療マウス IFN-γ 扁平上皮癌 pam212 抗腫瘍効果

项目摘要

Increased number of oral cancer patient is currently consideration, which in Spite of developing operation technique and chemotherapy. Cancer gene therapy is one of new approaches against oral cancer. Initiation of the adaptive immune response is believed to be a result of local necrotic and apoptotic death of tissues and release of inflammatory cytokines by resident macrophages and recruited plymorphonuclear leukocytes. The cytokines released at the tumor site include IL-1, IL-6, IL-12 and IL-18, and other cytokines and chemokines. Dendritic cell recruitment and maturation is required for the induction of immune response. IL-18, INF-g-inducing factor, is a stimulatory factor in activation of Th1 cells that are major INF-g producing cells at tumor site. INF-g is up-regulate MHC class I and II expression on tumor cells. MHC class I is activated NK cells and macrophages and to help generate CD8+ cytotoxic T cells. In this study, IL-18 gene transfer to mouse squamous cell carcinoma cell (PAM212) was used to deliver cytokine to the tumor microenvironment. IL-18 single gene transfection of tumor cell ex vivo resulted in minimum effect of tumor regression, To generate active form of IL-18, it needs to IL-1b converting enzyme (ICE) to cleaved intercellular cysteine residue. Thus, dual transfection of IL-18 and ICE was performed in this study. Dual gene transfection study of tumor cell ex vivo resulted in 20% effect of tumor regression that was out of our respect. The reason of these results may be related to the transfection efficiency of the genes to PAM212 cells. We also injected ICE to IL-18/PAM212 bearing mouse, resulted in death of all animals because of toxicity. Therefore, future study required for develop the technique of transfection efficiency in the squamous cell carcinoma.

尽管手术技术和化疗不断发展，口腔癌患者的数量仍在增加。癌症基因治疗是口腔癌治疗的新途径之一。适应性免疫反应的启动被认为是组织局部坏死和凋亡的结果，以及驻留的巨噬细胞和募集的增型核白细胞释放炎症细胞因子。肿瘤部位释放的细胞因子包括IL-1、IL-6、IL-12、IL-18等细胞因子和趋化因子。树突状细胞的募集和成熟是诱导免疫应答所必需的。IL-18，即INF-g诱导因子，是激活肿瘤部位主要产生INF-g的细胞Th1细胞的刺激因子。nf -g上调肿瘤细胞MHC I类和II类的表达。MHC I类激活NK细胞和巨噬细胞，帮助生成CD8+细胞毒性T细胞。本研究通过IL-18基因转移至小鼠鳞状细胞癌细胞（PAM212），将细胞因子传递至肿瘤微环境。IL-18单基因在体外转染肿瘤细胞，对肿瘤消退的影响最小，要产生活性形式的IL-18，需要IL-1b转化酶（ICE）裂解细胞间半胱氨酸残基。因此，本研究采用IL-18和ICE双转染。肿瘤细胞体外双基因转染研究，肿瘤消退率达到20%，超出了我们的预期。这些结果的原因可能与基因转染PAM212细胞的效率有关。我们也将ICE注射到携带IL-18/PAM212的小鼠体内，结果所有动物均因毒性而死亡。因此，未来的研究需要进一步发展鳞状细胞癌的转染效率技术。