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J.Y. Niederkorn, D.S. Dace, P.W. Chen, H. Alizadeh; Role of Interferon–Gamma in Intraocular Tumor Rejection . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2920.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the role of interferon–γ (IFN–γ) in the CD4+ T cell–dependent immune rejection of intraocular tumors in syngeneic mice.
An adenovirus–induced C57BL/6 embryonic tumor (Ad5E1) was transplanted into the eyes of wild–type C57BL/6 mice and various C57BL/6 knockout (KO) mice. IFN–γ production by CD4+ T cells was measured by ELISA and IFN–γ receptor expression on tumor cells was assessed by flow cytometry. Density of intraocular tumor blood vessels was measured by the FITC–dextran content of enucleated tumor–containing and normal eyes in mice injected i.v. with FITC–dextran. Tumor cell expression of pro– and anti–angiogenic genes was assessed by microarray.
Tumor rejection proceeded unabatedly in TRAIL KO mice, CD8 KO mice, and IFN–γ receptor KO mice, while tumors grew progressively in CD4 KO mice, IFN–γ KO mice, and ß2 microglobulin (ß2M) KO mice. CD4+ T cells from wild–type tumor rejector mice produced IFN–γ when stimulated with x–irradiated tumor cells in vitro. By contrast, CD4+ T cells from ß2M KO mice failed to produce detectable IFN–γ following in vitro stimulation with tumor cells. In wild–type mice, tumor rejection was accompanied by a sharp decrease in the intraocular tumor vasculature, while tumor progression in ß2 microglobulin KO mice correlated with a sharp increase in the density of tumor blood vessels. Tumor cells exposed to IFN–γ demonstrated a 3 to 27 fold increase in the expression of 5 anti–angiogenic genes and a 3 to 12 fold decrease in the expression of 4 pro–angiogenic genes.
In this model, IFN–γ exerts its anti–tumor effect via IFN–γ receptors on tumor cells, but not on the host’s immune cells. IFN–γ acts directly on the tumor cells and induces a sharp increase anti–angiogenic gene expression and a steep decrease in pro–angiogenic gene expression. Tumor rejection appears to be mediated by CD4+ T cell–produced IFNγ, which promotes tumor resolution by inhibiting angiogenesis of the intraocular tumors.
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