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

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

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 1

Disease stabilization in TNFR1 bone marrow chimeras.

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Disease stabilization in TNFR1 bone marrow chimeras. (A) TNFR1–/– bone m...
(A) TNFR1–/– bone marrow, WT bone marrow, and reverse (WT bone marrow in TNFR1–/– mice) chimeras were i.p. injected with 107 ID8 cells/mouse. Tumor burden was monitored weekly in situ by bioluminescence. TNFR1–/– bone marrow chimeras had significantly lower disease burden, starting 4 weeks after tumor cell injection (P < 0.01). Data are represented as mean ± SEM of n = 12. Representative data are shown from 2 independent experiments. (B) Total cell counts in the malignant ascites at week 8. Cytospins were prepared from ascitic fluid, and cells were differentiated with Wright’s staining. TNFR1–/– bone marrow chimeras had a significantly lower neutrophil infiltrate in the peritoneal cavity (P < 0.05, n = 12). Data are represented as mean ± SD of n = 12. Representative data are shown from 2 independent experiments. Data for WT (control mice, no chimeras) and reverse chimeras are shown in Supplemental Figure 1. (C) FACS analysis of the ascitic leukocyte infiltrate. TNFR1–/– bone marrow chimeras had significantly fewer infiltrating Gr-1+ F4/80– neutrophils (P < 0.01, n = 6). Data are represented as percentage of the CD45+ population, including mean of n = 6. Representative data are shown from 2 independent experiments (week 8). (D) WT mice were injected with 107 ID8-luc cells i.p.; Gr-1–neutralizing antibody or IgG control antibody were commenced twice weekly i.p. (100 μg/mouse). Data are represented as mean + SEM of n = 6. Representative data are shown from 2 independent experiments (week 8).