The antitumor effects of adenoviral-mediated, intratumoral delivery of interleukin 23 require endogenous IL-12

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Cancer gene therapy (Impact Factor: 2.55). 12/2011; 19(2):135-43. DOI: 10.1038/cgt.2011.78
Source: PubMed

ABSTRACT Interleukin (IL)-23 is a member of the IL-12 family of heterodimeric cytokines, comprised of p19 and p40 subunits, which exhibits immunostimulatory properties similar to IL-12. We have demonstrated previously that adenoviral-mediated, intratumoral delivery of IL-23 (Ad.IL-23) was able to induce systemic antitumor immunity. Here we demonstrate that Ad.IL-23 requires endogenous IL-12 for conferring an antitumor effect after adenoviral-mediated, intratumoral delivery. In contrast, Ad.IL-12 does not require IL-23 for its antitumor effects although endogenous IL-23 appears important for induction of systemic antitumor immunity by IL-12. However, despite the requirement for endogenous IL-12, co-delivery of IL-23 and IL-12 does not provide even an additive local or systemic antitumor effect, regardless of the dose. We further demonstrate that although the use of a single-chain IL-23 (scIL-23) results in higher level of expression and a more pronounced IL-23-mediated antitumor effect, there is still no synergy with IL-12. These results demonstrate that although significant antitumor effects are achieved by intratumoral injection of adenovirus expressing either scIL-23 or IL-12 alone and that IL-23 requires endogenous IL-12 for maximum antitumor benefit, the combined use of these cytokines provides no additive or synergistic effect.

Download full-text


Available from: Andrea Gambotto, Sep 10, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin (IL)-12 and IL-23 share the IL-12p40 molecule. IL-12 promotes T helper (Th)1 immunity and IL-23 promotes Th17 immunity, and it has recently become apparent that the balance between IL-12 and IL-23 is important in carcinogenesis. A series of studies demonstrated that, where tumor initiation, growth, and metastasis are concerned, IL-12 may act independently of interferon (IFN)-γ, and IL-23 independently of IL-17A. This review explores the activity of IL-23 in carcinogenesis. In the context of the tumor-inhibitory effects of IL-12, and tumor-promoting effects of IL-23, we discuss the use of anti-IL-12p/23 monoclonal antibodies (mAbs) in autoimmune inflammatory disorders and the alternative specific neutralization of IL-23.
    Trends in Immunology 08/2013; DOI:10.1016/ · 12.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.Cell Death and Differentiation advance online publication, 5 September 2014; doi:10.1038/cdd.2014.134.
    Cell Death and Differentiation 09/2014; 22(2). DOI:10.1038/cdd.2014.134 · 8.39 Impact Factor