Suppression of hepatocarcinogenesis by activating natural killer T cells

先天免疫反应是抵御癌变的第一道防线。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引发肝脏抗肿瘤免疫尤为重要。本研究探讨了α - galcer或先天细胞因子基因对小鼠肝脏肿瘤的抗肿瘤作用。给药αGalCer（一种Va14 NKT细胞受体的配体）完全抑制了同基因小鼠肝脏中弥散性BNL肝癌细胞的生长。α - galcer快速激活肝脏NKT细胞，随后延长NK细胞的激活时间。抗亚洲蓟GM1抗体在体内消耗NK细胞完全取消了治疗效果。注射编码IFNα基因或pIL-12基因的裸质粒DNA，而非模拟质粒，有效激活肝脏NK细胞1周，完全根除CT-26结肠癌细胞的肝转移。排斥反应依赖于NK细胞的存在，因为通过注射asialoGM1抗体在体内消耗NK细胞会消除这两种基因疗法的抗肿瘤活性。两种治疗方法均保护小鼠免受肝肿瘤的侵袭，皮下接种原肿瘤细胞。注射α galcer或pil -12的小鼠完全排斥再激肿瘤细胞，注射pifna的小鼠部分排斥再激肿瘤细胞。本研究发现，注射α - galcer和天然细胞因子基因如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反应有效地诱导了对原始肿瘤细胞的获得性免疫反应。

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.