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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CD4-Positive T-Lymphocytes / metabolism*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Culture Media, Conditioned
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1beta / physiology*
  • Interleukins / biosynthesis*
  • Interleukins / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neoplasm Transplantation
  • Signal Transduction
  • Tumor Burden

Substances

  • Culture Media, Conditioned
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Interleukins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • interleukin-22