hIFN-α gene modification augments human natural killer cell line anti-human hepatocellular carcinoma function

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-alpha (IFN-alpha) 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-alpha gene-modified natural killer cell line (NKL) (NKL-IFN alpha) cells, which could stably secrete IFN-alpha, were established. We investigated the natural cytotoxicity of NKL-IFN alpha cells against human hepatocarcinoma cells (HCCs) in vitro and in vivo. NKL-IFN alpha 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-IFN alpha 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-IFN alpha cells, such as tumor necrosis factor-alpha and IFN-gamma, 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-IFN alpha 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-alpha gene-modified NKL cells could be suitable for the future development of cell-based immunotherapeutic strategies for hepatocellular carcinoma.