Interleukin- 18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity

• Published in: Gene therapy Vol. 7; no. 19; pp. 1672 - 1679
• Main Authors: JU, D. W, YANG, Y, TAO, O, SONG, W. G, HE, L, CHEN, G, GU, S, TING, C. C, CAO, X
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2000
• Subjects: Adenoviridae - genetics; Adenoviruses; Animals; Antitumor activity; Biological and medical sciences; Biotechnology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cytokines; Cytosine; Cytosine Deaminase; Cytotoxicity; Female; Fundamental and applied biological sciences. Psychology; Gene therapy; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Health. Pharmaceutical industry; Histocompatibility antigen H-2; Industrial applications and implications. Economical aspects; Interferon-gamma - immunology; Interleukin 18; Interleukin 2; Interleukin-18 - genetics; Interleukin-2 - immunology; Killer Cells, Natural - immunology; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Major histocompatibility complex; Male; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Nucleoside Deaminases - genetics; Spleen; Suicide; Suicide genes; γ-Interferon; Antineoplastic agent; Animal model; Adenoviridae; Enzyme; Cytosine deaminase; Cytokine; Rodentia; Melanoma; Suicide gene; Immunity; Interleukin 18; Virus; Vertebrata; Mammalia; Mouse; Hydrolases; Tumor; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301291

To increase the antitumor effects of cytosine deaminase (AdCD) gene therapy and induce more potent antitumor immunity, Th1 cytokine interleukin-18 encoded adenovirus (AdIL18) was combined with adenovirus encoding CD (AdCD) for the therapy of established murine B16 melanoma. Combination therapy of the tumor-bearing mice with AdIL 18 and AdCD/5FC inhibited the growth of the subcutaneous B16 tumors more significantly, compared with AdIL 18 or AdCD/5FC alone. In vivo depletion analysis with anti-CD4, anti-CD8 or anti-NK 1.1 McAb illustrated that both CD8+ T cells and CD4+ T cells played key roles in the augmented antitumor response of the combined therapy. Peptide/MHC tetramer represents a powerful and general tool for rapid, highly sensitive, and direct analysis of antigen-specific T cells. In this study, we prepared H-2Kb/TRP-2180-188 tetramer, which was demonstrated to bind H-2Kb-restricted, B16 melanoma-specific CD8+ T cells. B16 specific H-2Kb/TRP2180-188 tetramer was used to stain the tumor-specific CD8+ T cells and the results showed that CD8+ tetramer+ T cells were about 3-5% of the splenic CD8+ T cells derived from tumor-bearing mice after combined therapy. The CTL cytotoxicity was markedly induced in mice after combined therapy, suggesting efficient induction of tumor-specific CD8+ T cells after combined gene therapy with AdCD/5FC/AdIL18. IL-18 gene transfer could significantly augment the cytotoxicity of NK cells and macrophages, and increase the production of interleukin-2 and interferon-gamma, as compared with treatments with AdCD/5FC, AdlacZ/5FC or PBS. These data suggested that in vivo IL-18 gene transfer could augment the antitumor effects of CD suicide gene therapy through efficient induction of antitumor immunity.