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The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans
Kellie A. Charles, … , Frances R. Balkwill, Thorsten Hagemann
Kellie A. Charles, … , Frances R. Balkwill, Thorsten Hagemann
Published September 8, 2009
Citation Information: J Clin Invest. 2009;119(10):3011-3023. https://doi.org/10.1172/JCI39065.
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Research Article Oncology Article has an altmetric score of 3

The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans

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Abstract

Cytokines orchestrate the tumor-promoting interplay between malignant cells and the immune system. In many experimental and human cancers, the cytokine TNF-α 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-α 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-α–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-α signaling pathway in ovarian cancer biopsy samples, showing particularly high levels of expression of genes encoding IL-23, components of the NF-κB system, TGF-β1, and proteins involved in neutrophil activation. We conclude that chronic production of TNF-α 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.

Authors

Kellie A. Charles, Hagen Kulbe, Robin Soper, Monica Escorcio-Correia, Toby Lawrence, Anne Schultheis, Probir Chakravarty, Richard G. Thompson, George Kollias, John F. Smyth, Frances R. Balkwill, Thorsten Hagemann

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Figure 4

Increased IL-17–dependent neutrophil recruitment.

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Increased IL-17–dependent neutrophil recruitment.
(A) Recombinant IL-17 ...
(A) Recombinant IL-17 rescued the antitumor effect in TNFR1flcneo mice (P < 0.01). Data are represented as mean ± SEM of n = 6. Representative data are shown from 2 independent experiments. The right-hand graph demonstrates the curves for only TNFR1cneo mice with or without recombinant IL-17. (B) Total cell counts of the leukocyte infiltrate in the malignant ascites at week 8 (after i.p. injection). Control (left): significantly lower neutrophils in TNFR1flcneo ID8 tumor–bearing mice compared with WT mice (P < 0.01). Treatment with recombinant murine IL-17A (0.5 μg/mouse/week; right): recombinant IL-17A rescued neutrophil infiltration in TNFR1flcneo ID8 tumor–bearing mice. Data are represented as mean + SD of n = 6. Representative data are shown from 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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