title: The tumor-promoting actions of TNF-alpha 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-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.
authors.affiliation: 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.
authors.forename: Kellie A
authors.initials: KA
authors.lastname: Charles
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Robin
authors.initials: R
authors.lastname: Soper
authors.forename: Monica
authors.initials: M
authors.lastname: Escorcio-Correia
authors.forename: Toby
authors.initials: T
authors.lastname: Lawrence
authors.forename: Anne
authors.initials: A
authors.lastname: Schultheis
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.forename: Richard G
authors.initials: RG
authors.lastname: Thompson
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: John F
authors.initials: JF
authors.lastname: Smyth
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002678:Chimera / Q000235:genetics / Q000276:immunology; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000069285:Infliximab; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D053759:Interleukin-23; D018123:Receptors, Interleukin; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C528688:interleukin-23 receptor, mouse; D000069285:Infliximab