Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis

J Immunol. 2011 Mar 15;186(6):3462-71. doi: 10.4049/jimmunol.1002901. Epub 2011 Feb 7.

Abstract

Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1β and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1β KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of γ/δ T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / immunology
  • Carcinoma, Lewis Lung / pathology*
  • Carcinoma, Lewis Lung / prevention & control*
  • Cell Communication / genetics
  • Cell Communication / immunology*
  • Cell Line, Tumor
  • Immune Tolerance / genetics
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology
  • Interleukin-17 / deficiency
  • Interleukin-17 / physiology*
  • Interleukin-1beta / deficiency
  • Interleukin-1beta / physiology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Male
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology*
  • Melanoma, Experimental / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / immunology
  • Neoplasm Invasiveness / prevention & control

Substances

  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-1beta