IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy.
Systemic administration of IL-12 and intermittent doses of IL-2 induce complete regression of metastatic murine renal carcinoma. Here, we show that overt tumor regression induced by IL-12/pulse IL-2 is preceded by recruitment of CD8(+) T cells, vascular injury, disrupted tumor neovascularization, and apoptosis of both endothelial and tumor cells. The IL-12/IL-2 combination synergistically enhances cell surface FasL expression on CD8(+) T lymphocytes in vitro and induces Fas and FasL expression within tumors via an IFN-gamma-dependent mechanism in vivo. This therapy also inhibits tumor neovascularization and induces tumor regression by mechanisms that depend critically on endogenous IFN-gamma production and an intact Fas/FasL pathway. The ability of IL-12/pulse IL-2 to induce rapid destruction of tumor-associated endothelial cells and regression of established metastatic tumors is ablated in mice with a dysregulated Fas/FasL pathway. The common, critical role for endogenous IFN-gamma and the Fas/FasL pathway in early antiangiogenic effects and in antitumor responses suggests that early, cytokine-driven innate immune mechanisms and CD8(+) T cell-mediated responses are interdependent. Definition of critical early molecular events engaged by IL-12/IL-2 may provide new perspective into optimal therapeutic engagement of a productive host-antitumor immune response.
Wigginton
J M
JM
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Gruys
E
E
Geiselhart
L
L
Subleski
J
J
Komschlies
K L
KL
Park
J W
JW
Wiltrout
T A
TA
Nagashima
K
K
Back
T C
TC
Wiltrout
R H
RH
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000556:secondary* / Q000601:surgery; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D053222:Fas Ligand Protein; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009392:Nephrectomy; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D019014:fas Receptor / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007155:Immunologic Factors; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma