IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy.
IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy.
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DOI：
10.1172/jci10128
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发表时间：
2001-07
期刊：
影响因子：
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通讯作者：
J. Wigginton;E. Gruys;L. Geiselhart;J. Subleski;K. Komschlies;J. Park;T. Wiltrout;K. Nagashima
中科院分区：
文献类型：
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作者：
J. Wigginton;E. Gruys;L. Geiselhart;J. Subleski;K. Komschlies;J. Park;T. Wiltrout;K. Nagashima
全身给药IL-12和间歇给药IL-2可诱导转移性肾癌完全消退。在这里，我们发现IL-12/脉冲IL-2诱导的明显肿瘤消退之前，CD8(+) T细胞的募集、血管损伤、肿瘤新生血管的破坏以及内皮细胞和肿瘤细胞的凋亡。IL-12/IL-2联合在体外协同增强CD8(+) T淋巴细胞表面FasL表达，在体内通过ifn - γ依赖机制诱导肿瘤内Fas和FasL表达。该疗法还通过内源性ifn - γ产生和完整的Fas/FasL通路的机制抑制肿瘤新生血管并诱导肿瘤消退。在Fas/FasL通路失调的小鼠中，IL-12/脉冲IL-2诱导肿瘤相关内皮细胞快速破坏和已建立转移性肿瘤消退的能力被削弱。内源性ifn - γ和Fas/FasL通路在早期抗血管生成作用和抗肿瘤反应中共同的关键作用表明，早期细胞因子驱动的先天免疫机制和CD8(+) T细胞介导的反应是相互依存的。IL-12/IL-2参与的关键早期分子事件的定义可能为高产宿主抗肿瘤免疫反应的最佳治疗参与提供新的视角。
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.