In vivo antitumor effects of murine interferon- γ -inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites

Abstract

Interferon-gamma-inducing factor/interleukin-18 is a novel cytokine that reportedly augments natural killer (NK) activity in human and mouse peripheral blood mononuclear cell cultures in vitro and has recently been designated IL-18. In this study, IL-18 exhibited significant antitumor effects in BALB/c mice challenged intraperitoneally (i.p.) with syngeneic Meth A sarcoma when administered i.p. on days 1, 2 and 3 after challenge. Intravenous (i.v.) administration also induced antitumor effects in the tumor-bearing mice; however, subcutaneous (s.c.) administration did not. When mice were twice pretreated with 1 microg IL-18 3 days and 6 h before tumor challenge, all mice survived whereas control mice died within 3 weeks of challenge. Inhibitory effects on Meth A cell growth in vitro were not observed with either IL-18 or interferon gamma. The effects of IL-18 pretreatment were abrogated by abolition of NK activity after mice had been injected with anti-asialo GM1 antibody 48 h before and, 24 h and 72 h after tumor challenge. Mice pretreated with IL-18 and surviving tumor challenge resisted rechallenge with Meth A cells but could not reject Ehrlich ascites carcinoma, and spleen cells from the resistant mice, but not control mice, exhibited cytotoxic activity against Meth A cells in vitro after restimulation with mitomycin C-treated Meth A cells for 5 days. The effector cells in the spleen cell preparations from resistant mice appear to be CD4+ cells because cytolytic activity was significantly inhibited after depletion of this subset by monoclonal antibodies and complement. In conclusion, IL-18 exhibits in vivo immunologically (primarily NK) mediated antitumor effects in mice challenged with syngeneic Meth A sarcoma and induces immunological memory and the generation of cytotoxic CD4+ cells.

Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration

“…10 IL-18 also has in vivo antitumor effects against Meth A sarcoma. 11 These biological activities are similar to those of IL-12. In fact, IL-12 and IL-18 exhibit a remarkably synergistic effect on IFN-␥ induction by stimulated T cells.…”

“…They concluded that the cells responsible for the cytotoxic activity induced by IL-18 were CD4 ϩ T cells. 11 Dao et al also showed that IL-18 selectively enhances the Fas ligand-mediated cytotoxicity of T helper 1 cells. 33 Considering these reports and our data, CD4 ϩ T cells appear to be essential for the antitumor effects of IL-18.…”

Protective immunity is induced in murine colon carcinoma cells by the expression of interleukin-12 or interleukin-18, which activate type 1 helper T cells

“…However, previous studies have shown that depletion of NK cells from immunocompetent mice using anti-asialo GM1 Ab abrogated the IL-18-mediated antitumor effect. 31 (Table 2), secretion of IL-18 might be inefficient to fully activate the immunocompetent cells. We also found that the loss of tumorigenicity of Colon 26/IL-18 cells when they were inoculated s.c. in immunocompetent mice was abolished when mice were pretreated with anti-IL-12 Ab (data not shown).…”

Immunotherapy of cancer by IL-12-based cytokine combinations

“…IL-18 induces IFN-γ production, promotes Th1 cell development and NK activation [54], making this cytokine potentially beneficial as an immunotherapeutic agent against cancer. Indeed, IL-18 has been effective in various experimental tumor models [55][56][57]. However, IL-18 is also implicated in tumor progression.…”