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Suppression of hepatocarcinogenesis by activating natural killer T cells

通过激活自然杀伤 T 细胞抑制肝癌发生

基本信息

批准号：
14570468
负责人：
TAKEHARA Tetsuo
金额：
$ 2.18万
依托单位：
Osaka 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-14570468/
关键词：
natural killer cell natural killer T cell cancer liver α-galactosyl ceramide interleukin-12 interferon α innate immunity tumor 腫瘍肝癌 α-GalCer CDld IFN_γ 抗腫瘍免疫

项目摘要

Innate immune response serves as a first line of defense against carcinogenesis. Since lives contain lots of innate immune effector cells, such as NKT cells and NK cells, innate immune response may be especially important to elicit anti-tumor immunity in the liver. In the present study, we investigated anti-tumor effect elicited by administration of αGalCer or innate cytokine genes against liver tumors in mice. Administration of αGalCer, a ligand for Va14 NKT cell receptor, completely suppressed the growth of BNL hepatoma cells disseminated in the liver of syngeneic mice. αGalCer administration rapidly activated hepatic NKT cells followed by a prolonged activation of NK cells. In vivo depletion of NK cells by anti-asialo GM1 antibody completely abrogated the therapeutic effect. Injection of naked plasmid DNA encoding either IFNα gene or pIL-12 gene, but not mock plasmid, efficiently activated hepatic NK cells for 1 week and completely eradicated hepatic metastasis of CT-26 colon tumor cells. The rejection is dependent on the presence of NK cells, since in vivo depletion of NK cells by injecting asialoGM1 antibody abolished the anti-tumor activity of both gene therapies. The mice that had been protected from hepatic tumor by both therapies were challenged with subcutaneous inoculation of original tumor cells. αGalCer-or pIL-12-injected mice completely rejected re-challenged tumor cells, and pIFNa-injected mice did partially. The present study revealed that injection of αGalCer and innate cytokine genes such as IL-12 and IFNα protect from hepatic metastasis in a NKT cell or NK cell dependent manner. Furthermore, tumor rejection provoked by activation of innate immune cells efficiently induced acquired immune response against original tumor cells.

先天免疫反应是抵抗癌症发生的第一道防线。由于生命中含有大量的天然免疫效应细胞，如NKT细胞和NK细胞，因此天然免疫应答对于在肝脏中引发抗肿瘤免疫可能特别重要。在本研究中，我们研究了αGalCer或先天性细胞因子基因对小鼠肝肿瘤的抗肿瘤作用。给予Va 14 NKT细胞受体的配体αGalCer可完全抑制同系小鼠肝脏中播散的BNL肝癌细胞的生长。αGalCer给药快速激活肝脏NKT细胞，随后延长NK细胞的激活。通过抗脱唾液酸基GM 1抗体体内耗竭NK细胞完全消除了治疗效果。注射编码IFNα基因或pIL-12基因的裸质粒DNA（而不是模拟质粒）可有效激活肝脏NK细胞1周，并完全根除CT-26结肠肿瘤细胞的肝转移。排斥反应依赖于NK细胞的存在，因为通过注射脱唾液酸GM 1抗体体内消耗NK细胞消除了两种基因疗法的抗肿瘤活性。通过皮下接种原始肿瘤细胞来攻击通过两种疗法保护免于肝肿瘤的小鼠。注射α GalCer或pIL-12的小鼠完全排斥再激发的肿瘤细胞，而注射pIFNa的小鼠部分排斥。目前的研究表明，注射αGalCer和先天性细胞因子基因如IL-12和IFNα以NKT细胞或NK细胞依赖的方式保护肝转移。此外，由先天免疫细胞激活引起的肿瘤排斥有效地诱导针对原始肿瘤细胞的获得性免疫应答。