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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / pharmacology
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / immunology*
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B-Lymphocytes / immunology
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Carcinoma, Lewis Lung / immunology*
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Carcinoma, Lewis Lung / pathology
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Carcinoma, Lewis Lung / prevention & control*
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Cells, Cultured
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Drug Synergism
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Fas Ligand Protein
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Injections, Intraperitoneal
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Interferon-gamma / biosynthesis*
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Interferon-gamma / physiology
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Interleukin-12 / physiology
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Interleukin-18 / administration & dosage
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Interleukin-18 / pharmacology
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Interleukin-2 / administration & dosage
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Interleukin-2 / pharmacology
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Killer Cells, Natural / immunology
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Ligands
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, SCID
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Remission Induction
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Signal Transduction / immunology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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T-Lymphocyte Subsets / immunology
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fas Receptor / metabolism*
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fas Receptor / physiology
Substances
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Adjuvants, Immunologic
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Fas Ligand Protein
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Fasl protein, mouse
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Interleukin-18
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Interleukin-2
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Ligands
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Membrane Glycoproteins
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fas Receptor
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Interleukin-12
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Interferon-gamma