Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation

J Clin Invest. 2013 Nov;123(11):4859-74. doi: 10.1172/JCI65180.

Abstract

The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Humans
  • Immunotherapy / adverse effects
  • Inflammation / etiology
  • Inflammation / immunology*
  • Inflammation / prevention & control
  • Interferon Type I / metabolism*
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / deficiency
  • Interleukin-10 / genetics
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • STAT1 Transcription Factor / deficiency
  • STAT1 Transcription Factor / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*

Substances

  • IL10 protein, human
  • IL10 protein, mouse
  • Ifnar1 protein, mouse
  • Il17a protein, mouse
  • Interferon Type I
  • Interleukin-17
  • RNA, Messenger
  • RNA, Neoplasm
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interleukin-10
  • Receptor, Interferon alpha-beta