The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans
The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans
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DOI：
10.1172/jci39065
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Hagemann, Thorsten
中科院分区：
文献类型：
--
作者：
Charles, Kellie A.;Kulbe, Hagen;Hagemann, Thorsten
细胞因子协调恶性细胞和免疫系统之间的肿瘤促进相互作用。在许多实验和人类癌症中，细胞因子TNF-α是这种相互作用的重要组成部分，但其作用是多效性的，因此仍有待完全确定。使用卵巢癌的小鼠模型，其中在不同的白细胞群体或TNF-α中操纵TNF受体1（TNFR 1）信号传导。被抗体治疗中和，我们发现这种炎性细胞因子维持CD 4（+）细胞产生TNFR 1依赖性IL-17，这导致骨髓细胞募集到肿瘤微环境中并增强肿瘤生长。与此一致，在晚期癌症患者中，用TNF-α特异性抗体英夫利西单抗治疗显著降低了血浆IL-17水平。此外，从接受英夫利西单抗治疗的卵巢癌患者腹水中分离的CD 4（+）CD 25（-）细胞中IL-1 R和IL-23 R的表达下调。我们还发现，在卵巢癌活检样本中，属于Th 17通路的基因与TNF-α信号通路密切相关，显示编码IL-23、NF-κ B系统组分、TGF-β 1和参与中性粒细胞活化的蛋白质的基因表达水平特别高。我们的结论是，肿瘤微环境中TNF-α的慢性产生以IL-17依赖的方式增加了骨髓细胞的募集，这有助于这种促炎细胞因子的促肿瘤作用。
Cytokines orchestrate the tumor-promoting interplay between malignant cells and the immune system. In many experimental and human cancers, the cytokine TNF-alpha is an important component of this interplay, but its effects are pleiotropic and therefore remain to be completely defined. Using a mouse model of ovarian cancer in which either TNF receptor 1 (TNFR1) signaling was manipulated in different leukocyte populations or TNF-alpha. was neutralized by antibody treatment, we found that this inflammatory cytokine maintained TNFR1-dependent IL-17 production by CD4(+) cells and that this led to myeloid cell recruitment into the tumor microenvironment and enhanced tumor growth. Consistent with this, in patients with advanced cancer, treatment with the TNF-alpha-specific antibody infliximab substantially reduced plasma IL-17 levels. Furthermore, expression of IL-1R and IL-23R was downregulated in CD4(+)CD25(-) cells isolated from ascites of ovarian cancer patients treated with infliximab. We have also shown that genes ascribed to the Th17 pathway map closely with the TNF-alpha signaling pathway in ovarian cancer biopsy samples, showing particularly high levels of expression of genes encoding IL-23, components of the NF-kappa B system, TGF-beta 1, and proteins involved in neutrophil activation. We conclude that chronic production of TNF-alpha in the tumor microenvironment increases myeloid cell recruitment in an IL-17-dependent manner that contributes to the tumor-promoting action of this proinflammatory cytokine.