title: Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis.
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.
authors.affiliation: Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Carmi
authors.forename: Gal
authors.initials: G
authors.lastname: Rinott
authors.forename: Shahar
authors.initials: S
authors.lastname: Dotan
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.forename: Peleg
authors.initials: P
authors.lastname: Rider
authors.forename: Elena
authors.initials: E
authors.lastname: Voronov
authors.forename: Ron N
authors.initials: RN
authors.lastname: Apte
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D007108:Immune Tolerance / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D020381:Interleukin-17 / Q000172:deficiency / Q000502:physiology*; D053583:Interleukin-1beta / Q000172:deficiency / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000276:immunology / Q000517:prevention & control
chemical_list: D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta