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and Fas-Ligand-Dependent Tumor Eradication by Combined Administration of IL-18 and IL-21
* Pediatric Oncology Branch,
Laboratory of Experimental Immunology, and
Data Management Services, National Cancer Institute-Center for Cancer Research, Bethesda, MD 20892; and
Intramural Research Support Program, Science Applications International Corporation-Frederick, Frederick, MD 21702
IFN-
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- 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- 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-, and the
Fas/Fas-L pathway. These studies demonstrate the importance of IFN-
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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