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

• Published in: The Journal of immunology (1950) 2002-10, Vol.169 (8), p.4467-4474
• Main Authors: Wigginton, Jon M, Lee, Jong-Keuk, Wiltrout, Theresa A, Alvord, W. Gregory, Hixon, Julie A, Subleski, Jeffrey, Back, Timothy C, Wiltrout, Robert H
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

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 super(+) 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.