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Cancer cells induce interleukin-22 production from memory CD4⁺ T cells via interleukin-1 to promote tumor growth.

ABSTRACT: IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4⁺ T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of IL-1? from both myeloid and T cells. IL-1 receptor signaling via the transcription factors AhR and ROR?t in T cells was necessary and sufficient for IL-22 production. In these settings, IL-1 induced IL-22 production from a mixed T helper cell population comprised of Th1, Th17, and Th22 cells, which was abrogated by the addition of anakinra. We confirmed these findings in vitro and in vivo in two murine tumor models, in primary human breast and lung cancer cells, and in deposited expression data. Relevant to ongoing clinical trials in breast cancer, we demonstrate here that the IL-1 receptor antagonist anakinra abrogates IL-22 production and reduces tumor growth in a murine breast cancer model. Thus, we describe here a previously unrecognized mechanism by which cancer cells induce IL-22 production from memory CD4⁺ T cells via activation of the NLRP3 inflammasome and the release of IL-1? to promote tumor growth. These findings may provide the basis for therapeutic interventions that affect IL-22 production by targeting IL-1 activity.

SUBMITTER: Voigt C

PROVIDER: S-EPMC5724250 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Cancer cells induce interleukin-22 production from memory CD4<sup>+</sup> T cells via interleukin-1 to promote tumor growth.

Voigt Cornelia C May Peter P Gottschlich Adrian A Markota Anamarija A Wenk Daniel D Gerlach Inga I Voigt Sebastian S Stathopoulos Georgios T GT Arendt Kristina A M KAM Heise Constanze C Rataj Felicitas F Janssen Klaus-Peter KP Königshoff Melanie M Winter Hauke H Himsl Isabelle I Thasler Wolfgang E WE Schnurr Max M Rothenfußer Simon S Endres Stefan S Kobold Sebastian S

Proceedings of the National Academy of Sciences of the United States of America 20171117 49

IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4<sup>+</sup> T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of ...[more]

PMID: 29150554

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Project description:Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP.We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses.Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I ?1 chain, but not ?2 smooth muscle actin or transforming growth factor-?. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers.AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

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Cancer cells induce interleukin-22 production from memory CD4⁺ T cells via interleukin-1 to promote tumor growth.

Publications

Cancer cells induce interleukin-22 production from memory CD4<sup>+</sup> T cells via interleukin-1 to promote tumor growth.

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Cancer cells induce interleukin-22 production from memory CD4+ T cells via interleukin-1 to promote tumor growth.

Publications

Cancer cells induce interleukin-22 production from memory CD4<sup>+</sup> T cells via interleukin-1 to promote tumor growth.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cancer cells induce interleukin-22 production from memory CD4⁺ T cells via interleukin-1 to promote tumor growth.