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PMID: 19741298 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 119 ·No. 10 ·2009-10-00 ·Pages 3011-23

Charles KA, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A, Chakravarty P, Thompson RG, Kollias G, Smyth JF, Balkwill FR, Hagemann T

Abstract

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-kappaB system, TGF-beta1, 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.

MeSH Terms
Animals Anti-Inflammatory Agents/therapeutic use Antibodies, Monoclonal/therapeutic use CD4-Positive T-Lymphocytes/immunology Chimera/genetics,immunology Clinical Trials as Topic Disease Models, Animal Female Gene Expression Profiling Humans Infliximab Interleukin-17/genetics,immunology Interleukin-2 Receptor alpha Subunit/genetics,immunology Interleukin-23/genetics,immunology Mice Mice, Inbred C57BL Mice, Knockout Microarray Analysis Ovarian Neoplasms/drug therapy,genetics,immunology Receptors, Interleukin/genetics,immunology Receptors, Tumor Necrosis Factor, Type I Signal Transduction/physiology Tumor Necrosis Factor-alpha/genetics,immunology
Chemicals
Anti-Inflammatory Agents Antibodies, Monoclonal Interleukin-17 Interleukin-2 Receptor alpha Subunit Interleukin-23 Receptors, Interleukin Receptors, Tumor Necrosis Factor, Type I Tumor Necrosis Factor-alpha interleukin-23 receptor, mouse Infliximab
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Charles Kellie A
Centre for Cancer and Inflammation, Institute of Cancer, Barts and The London School of Medicine and Dentistry,Queen Mary University of London, Charterhouse Square, London, United Kingdom.
Kulbe Hagen
Soper Robin
Escorcio-Correia Monica
Lawrence Toby
Schultheis Anne
Chakravarty Probir
Thompson Richard G
Kollias George
Smyth John F
Balkwill Frances R
Hagemann Thorsten
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI39065
Published
2009-10-00
Epub
2009-00-08
Pages
3011-23
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2752076
Subset
IM
Grants
Medical Research Council · G0501974 · United Kingdom
Medical Research Council · G0601867 · United Kingdom
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1172/JCI39065 PMC Full Text View journal details
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