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.
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.
Wigginton
Jon M
JM
Pediatric Oncology Branch, National Cancer Institute-Center for Cancer Research, Building 560, Room 31-93, Bethesda, MD 20892, USA. jw121b@nih.gov
Lee
Jong-Keuk
JK
Wiltrout
Theresa A
TA
Alvord
W Gregory
WG
Hixon
Julie A
JA
Subleski
Jeffrey
J
Back
Timothy C
TC
Wiltrout
Robert H
RH
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004357:Drug Synergism; D053222:Fas Ligand Protein; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D012074:Remission Induction; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism* / Q000502:physiology
D000276:Adjuvants, Immunologic; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020382:Interleukin-18; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma