Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNalpha gene to mice.
Interferon (IFN) alpha is a pleiotropic cytokine acting as an antiviral substance, cell growth inhibitor and immunomodulator. To evaluate the therapeutic efficacy and mechanisms of IFNalpha on hepatic metastasis of tumor cells, we hydrodynamically injected naked plasmid DNA encoding IFNalpha1 (pCMV-IFNa1) into Balb/cA mice having 2 days hepatic metastasis of CT-26 cells. Single injection of pCMV-IFNa1 efficiently enhanced the natural killer (NK) activity of hepatic mononuclear cells, induced production of IFNgamma in serum and led to complete rejection of tumors in the liver. Mice protected from hepatic metastasis by IFNalpha therapy displayed a tumor-specific cytotoxic T cell response and were resistant to subcutaneous challenge of CT-26 cells. NK cells were critically required for IFNalpha-mediated rejection of hepatic metastasis, because their depletion by injecting anti-asialo GM1 antibody completely abolished the antimetastatic effect. To find whether NK cells are directly activated by IFNalpha and are sufficient for the antimetastatic effect, the responses to IFNalpha were examined in SCID mice lacking T cells, B cells and NKT cells. IFNalpha completely rejected hepatic metastasis in SCID mice and efficiently activated SCID mononuclear cells, as evidenced by activation of STAT1 and a variety of genes, such as MHC class I, granzyme B, tumor necrosis factor-related apoptosis-inducing ligand and IFNgamma, and also enhanced Yac1 lytic ability. Study of IFNgamma knockout mice revealed that IFNgamma was not necessary for IFNalpha-mediated NK cell activation and metastasis protection. In conclusion, IFNalpha efficiently activates both innate and adaptive immune responses, but NK cells are critically required and sufficient for IFNalpha-mediated initial rejection of hepatic metastasis of microdisseminated tumors.
Takehara
Tetsuo
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suiuta, Osaka 565-0871, Japan.
Uemura
Akio
A
Tatsumi
Tomohide
T
Suzuki
Takahiro
T
Kimura
Ritsuko
R
Shiotani
Ai
A
Ohkawa
Kazuyoshi
K
Kanto
Tatsuya
T
Hiramatsu
Naoki
N
Hayashi
Norio
N
D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D007267:Injections; D007371:Interferon-gamma / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology
D007371:Interferon-gamma