Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
Gene Ther. 2013 Nov;20(11):1062-9. doi: 10.1038/gt.2013.31. Epub 2013 Jun 13.
Natural killer (NK) cells are characterized by an efficient antitumor activity, and this activity has been exploited as the basis of cancer immunotherapy strategies. Interferon-α (IFN-α) is an important cytokine required for induction of the durable antitumor immune response and is an important stimulator of NK cells. In this study, to augment the efficiency of NK cell cytotoxicity to tumor cells, human IFN-α gene-modified natural killer cell line (NKL) (NKL-IFNα) cells, which could stably secrete IFN-α, were established. We investigated the natural cytotoxicity of NKL-IFNα cells against human hepatocarcinoma cells (HCCs) in vitro and in vivo. NKL-IFNα cells displayed a significantly stronger cytolytic activity against both human HCC cell lines and primary human hepatoma cancer cells compared with parental NKL cells. The increased cytolytic activity of NKL-IFNα cells was associated with the upregulation of cytotoxicity-related genes, such as perforin, granzyme B and Fas ligand, in the NK cells. Moreover, cytokines secreted by NKL-IFNα cells, such as tumor necrosis factor-α and IFN-γ, induced increased expression of Fas on the target HCC cells, and resulted in increased susceptibility of the HCC cells to NK-mediated cytolysis. Encouragingly, NKL-IFNα cells could significantly inhibit HCC tumor growth in a xenograft model and prolonged the survival of tumor-bearing nude mice. These results suggest that IFN-α gene-modified NKL cells could be suitable for the future development of cell-based immunotherapeutic strategies for hepatocellular carcinoma.
自然杀伤 (NK) 细胞具有高效的抗肿瘤活性，这种活性已被用作癌症免疫治疗策略的基础。干扰素-α (IFN-α) 是诱导持久抗肿瘤免疫反应所必需的重要细胞因子，也是 NK 细胞的重要刺激物。在这项研究中，为了提高 NK 细胞对肿瘤细胞的细胞毒性效率，建立了能够稳定分泌 IFN-α的人 IFN-α 基因修饰的自然杀伤细胞系 (NKL) (NKL-IFNα) 细胞。我们研究了 NKL-IFNα 细胞在体外和体内对人肝癌细胞 (HCC) 的自然细胞毒性。与亲本 NKL 细胞相比，NKL-IFNα 细胞对两种人 HCC 细胞系和原发性人肝癌细胞表现出更强的细胞毒性。NKL-IFNα 细胞的细胞毒性增强与 NK 细胞中细胞毒性相关基因（如穿孔素、颗粒酶 B 和 Fas 配体）的上调有关。此外，NKL-IFNα 细胞分泌的细胞因子，如肿瘤坏死因子-α和 IFN-γ，诱导靶 HCC 细胞上 Fas 的表达增加，导致 HCC 细胞对 NK 介导的细胞溶解的敏感性增加。令人鼓舞的是，NKL-IFNα 细胞可显著抑制异种移植模型中的 HCC 肿瘤生长，并延长荷瘤裸鼠的存活时间。这些结果表明，IFN-α 基因修饰的 NKL 细胞可能适合未来开发用于肝细胞癌的细胞免疫治疗策略。
