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

• Published in: The Journal of clinical investigation 2009-10, Vol.119 (10), p.3011-3023
• Main Authors: Charles, Kellie A, 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
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents - therapeutic use; Antibodies, Monoclonal; Antibodies, Monoclonal - therapeutic use; Care and treatment; CD4-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes - immunology; Chimera; Chimera - genetics; Chimera - immunology; Clinical Trials as Topic; Development and progression; Disease Models, Animal; Female; Gene Expression Profiling; Humans; Immunology; Infliximab; Interleukin-17; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-2 Receptor alpha Subunit; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-23; Interleukin-23 - genetics; Interleukin-23 - immunology; Interleukins; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Ovarian cancer; Ovarian Neoplasms; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Properties; Receptors, Interleukin; Receptors, Interleukin - genetics; Receptors, Interleukin - immunology; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Signal Transduction - physiology; Tumor necrosis factor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI39065

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.