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Patients with inflammatory bowel disease (IBD) have an increased risk of colon cancer. However, the immune cells and cytokines that mediate the transition from intestinal inflammation to cancer are poorly understood. We show that bacteria-induced colon cancer is accompanied by differential accumulation of IL-17(+)IL-22(+) colonic innate lymphoid cells (cILCs), which are phenotypically distinct from LTi and NK-22 cells, and that their depletion in mice with dysplastic inflammation blocks the development of invasive colon cancer. Analysis of the functional role of distinct Type 17 cytokines shows that although blockade of IL-17 inhibits some parameters of intestinal inflammation, reduction in dysplasia and colorectal cancer (CRC) requires neutralization of IL-22 indicating a unique role for IL-22 in the maintenance of cancer in this model. Mechanistic analyses showed that IL-22 selectively acts on epithelial cells to induce Stat3 phosphorylation and proliferation. Importantly, we could detect IL-22(+)CD3(+) and IL-22(+)CD3(−) cells in human CRC. Our results describe a new activity of IL-22 in the colon as a nonredundant mediator of the inflammatory cascade required for perpetuation of CRC, highlighting the IL-22 axis as a novel therapeutic target in colon cancer.

Original publication

DOI

10.1084/jem.20122308

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

05/2013

Volume

210

Pages

917 - 931

Addresses

Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Headington, Oxford OX3 9DU, UK

Keywords

Colon, Lymphocytes, Epithelial Cells, Animals, Humans, Mice, Helicobacter, Colonic Neoplasms, Cell Transformation, Neoplastic, Colitis, Disease Models, Animal, Disease Progression, Antigens, CD4, Antigens, Ly, Interleukins, Gene Expression Regulation, Neoplastic, Phosphorylation, Cell Lineage, STAT3 Transcription Factor, Natural Cytotoxicity Triggering Receptor 1