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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.

先天免疫反应是抵御致癌的第一道防线。由于生命中含有大量的先天免疫效应细胞，如NKT细胞和NK细胞，先天免疫反应可能对诱导肝脏的抗肿瘤免疫尤为重要。在本研究中，我们研究了αGalCer或天然细胞因子基因对小鼠肝肿瘤的抗肿瘤作用。给予Va14NKT细胞受体配体αGalCer可完全抑制同基因小鼠肝内播散的BNL型肝癌细胞的生长。αGalCer可迅速激活肝脏NKT细胞，随后可延长NK细胞的激活时间。体内用抗asialo GM1抗体去除NK细胞后，其治疗效果完全消失。注射含有干扰素α基因和pIL-12基因的裸质粒DNA，而不注射模拟载体，可有效激活肝脏NK细胞1周，并完全消除CT-26结肠癌细胞的肝转移。排斥反应依赖于NK细胞的存在，因为注射asialoGM1抗体在体内耗尽了NK细胞，从而消除了两种基因疗法的抗肿瘤活性。通过这两种疗法保护小鼠免受肝脏肿瘤的影响，然后对原始肿瘤细胞进行皮下接种。注射αGalCer或pIL-12的小鼠完全排斥再次挑战的肿瘤细胞，而注射pIFNa的小鼠则部分拒绝。本研究表明，αGalCer和天然细胞因子基因如IL-12和干扰素α的注射可通过依赖NKT细胞或NK细胞的方式保护小鼠的肝转移。此外，由天然免疫细胞激活引起的肿瘤排斥反应有效地诱导了对原始肿瘤细胞的获得性免疫反应。