Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Angiogenesis Inhibitors / administration & dosage
-
Angiogenesis Inhibitors / pharmacology*
-
Angiogenesis Inhibitors / therapeutic use
-
Animals
-
Antineoplastic Agents / administration & dosage
-
Antineoplastic Agents / pharmacology*
-
Antineoplastic Agents / therapeutic use
-
Apoptosis / drug effects
-
CD8-Positive T-Lymphocytes / immunology
-
Carcinoma, Renal Cell / blood supply
-
Carcinoma, Renal Cell / drug therapy
-
Carcinoma, Renal Cell / immunology
-
Carcinoma, Renal Cell / secondary*
-
Carcinoma, Renal Cell / surgery
-
Combined Modality Therapy
-
Drug Administration Schedule
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / pathology
-
Fas Ligand Protein
-
Immunologic Factors / administration & dosage
-
Immunologic Factors / pharmacology*
-
Immunologic Factors / therapeutic use
-
Injections, Intraperitoneal
-
Interferon-gamma / physiology*
-
Interleukin-12 / administration & dosage
-
Interleukin-12 / pharmacology*
-
Interleukin-12 / therapeutic use
-
Kidney Neoplasms / blood supply
-
Kidney Neoplasms / drug therapy*
-
Kidney Neoplasms / immunology
-
Kidney Neoplasms / pathology
-
Kidney Neoplasms / surgery
-
Membrane Glycoproteins / deficiency
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / physiology*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C3H
-
Mice, Knockout
-
Mice, Mutant Strains
-
Neoplasm Metastasis
-
Neoplasm Transplantation
-
Neovascularization, Pathologic / drug therapy*
-
Nephrectomy
-
Recombinant Proteins / administration & dosage
-
Recombinant Proteins / pharmacology
-
Recombinant Proteins / therapeutic use
-
Specific Pathogen-Free Organisms
-
fas Receptor / physiology*
Substances
-
Angiogenesis Inhibitors
-
Antineoplastic Agents
-
Fas Ligand Protein
-
Fasl protein, mouse
-
Immunologic Factors
-
Membrane Glycoproteins
-
Recombinant Proteins
-
fas Receptor
-
Interleukin-12
-
Interferon-gamma