Suppression of hepatocarcinogenesis by activating natural killer T cells

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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.