IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy
| Autor: | J M, Wigginton, E, Gruys, L, Geiselhart, J, Subleski, K L, Komschlies, J W, Park, T A, Wiltrout, K, Nagashima, T C, Back, R H, Wiltrout |
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| Rok vydání: | 2001 |
| Předmět: |
Fas Ligand Protein
Angiogenesis Inhibitors Antineoplastic Agents Apoptosis CD8-Positive T-Lymphocytes Nephrectomy Drug Administration Schedule Article Interferon-gamma Mice Animals Immunologic Factors fas Receptor Neoplasm Metastasis Carcinoma Renal Cell Mice Knockout Mice Inbred BALB C Mice Inbred C3H Membrane Glycoproteins Neovascularization Pathologic Combined Modality Therapy Interleukin-12 Kidney Neoplasms Mice Mutant Strains Recombinant Proteins Specific Pathogen-Free Organisms Endothelium Vascular Injections Intraperitoneal Neoplasm Transplantation |
| Zdroj: | The Journal of clinical investigation. 108(1) |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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