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Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):12994-12999. doi: 10.1073/pnas.1705165114. Epub 2017 Nov 17.

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

Voigt C1,2,3,4,5,6, May P1,2,6, Gottschlich A1,2,6, Markota A1,2,6, Wenk D1,2,6, Gerlach I1,2,6, Voigt S7, Stathopoulos GT3,4,6,8,9, Arendt KAM3,4,5,6, Heise C1,2,6, Rataj F1,2,6, Janssen KP10, Königshoff M3,4,5,6, Winter H6,11, Himsl I7, Thasler WE12, Schnurr M1,2,6, Rothenfußer S1,2,6, Endres S1,2,6, Kobold S13,2,6.

Author information

1
Center of Integrated Protein Science Munich, University Hospital, Ludwig Maximilian University of Munich, 80337 Munich, Germany.
2
Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig Maximilian University of Munich, 80337 Munich, Germany.
3
Comprehensive Pneumology Center, Ludwig Maximilian University of Munich, 80337 Munich, Germany.
4
Institute for Lung Biology and Disease, University Hospital, Ludwig Maximilian University of Munich, 80337 Munich, Germany.
5
Helmholtz Zentrum München, 81377 Munich, Germany.
6
German Center for Lung Research, 81377 Munich, Germany.
7
Brustzentrum Klinikum Dritter Orden, 80638 Munich, Germany.
8
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, University of Patras, Rio, Achaia, 26504 Greece.
9
Faculty of Medicine, University of Patras, Rio, Achaia, 26504 Greece.
10
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, 81675 Munich, Germany.
11
Department of Thoracic Surgery, University Hospital, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
12
Biobank, Department of General, Visceral and Transplantation Surgery, University Hospital, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
13
Center of Integrated Protein Science Munich, University Hospital, Ludwig Maximilian University of Munich, 80337 Munich, Germany; sebastian.kobold@med.uni-muenchen.de.

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-1β from both myeloid and T cells. IL-1 receptor signaling via the transcription factors AhR and RORγt 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-1β to promote tumor growth. These findings may provide the basis for therapeutic interventions that affect IL-22 production by targeting IL-1 activity.

KEYWORDS:

anakinra; cancer immunology; inflammasome; interleukin-1; interleukin-22

PMID:
29150554
PMCID:
PMC5724250
DOI:
10.1073/pnas.1705165114
[Indexed for MEDLINE]
Free PMC Article

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