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Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand- dependent tumor eradication by combined administration of IL-18 and IL-2

  1. Author:
    Wigginton, J. M.
    Lee, J. K.
    Wiltrout, T. A.
    Alvord, W. G.
    Hixon, J. A.
    Subleski, J.
    Back, T. C.
    Wiltrout, R. H.

  2. Author Address

    NCI, Pediat Oncol Branch, Bldg 560,Room 31-93, Frederick, MD 21702 USA Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA NCI, Pediat Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA NCI, Expt Immunol Lab, Canc Res Ctr, Bethesda, MD 20892 USA NCI, Data Management Serv, Canc Res Ctr, Bethesda, MD 20892 USA Wigginton JM NCI, Pediat Oncol Branch, Bldg 560,Room 31-93, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Journal of Immunology
    1. 169
    2. 8
    3. Pages: 4467-4474
  4. Type of Article: Article
  1. Abstract:

    IFN-gamma is a critical component of the endogenous and many cytokine-induced antitumor immune responses. In this study we have shown that the combination of IL-18 and IL-2 (IL-18/IL-2) synergistically enhances IFN-gamma production both in vitro and in vivo, and synergizes in vivo to induce complete durable regression of well-established 3LL tumors in > 80% of treated mice. We have observed a nascent, but ineffective, host immune response against 3LL that depends on endogenous IFN-gamma and IL-12 production and the Fas/Fas ligand (Fas-L) pathway. The combined administration of IL-18/IL-2 engages this endogenous response to induce tumor regression via a mechanism that is independent of NK and NKT cells or IL-12, but is critically dependent on CD8(+) T cells, IFN-gamma, and the Fas/Fas-L pathway. These studies demonstrate the importance of IFN-gamma as well as the Fas/Fas-L pathway in both endogenous and cytokine-driven antitumor immune responses engaged by IL-18/IL- 2 and provide preclinical impetus for clinical investigation of this potent anti-tumor combination.

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