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

Y Carmi, G Rinott, S Dotan, M Elkabets… - The Journal of …, 2011 - journals.aai.org
Y Carmi, G Rinott, S Dotan, M Elkabets, P Rider, E Voronov, RN Apte
The Journal of Immunology, 2011journals.aai.org
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 …
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.
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