title: A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment.
abstract: IL-17A, produced by Th17 cells, may play a dual role in antitumor immunity. Using the GL261-glioma model, we investigated the effects of Th17 cells on tumor growth and microenvironment. Th17 cells infiltrate mouse gliomas, increase significantly in a time-dependent manner similarly to Treg and do not express Foxp3. To characterize the direct effects of Th17 cells on GL261 murine gliomas and on tumor microenvironment, we isolated IL-17-producing cells enriched from splenocytes derived from naïve (nTh17) or glioma-bearing mice (gTh17) and pre-stimulated in vitro with or without TGF-β. Spleen-derived Th17 cells co-expressing IL-17, IFN-γ and IL-10, but not Treg marker Foxp3, were co-injected intracranially with GL261 in immune-competent mice. Mice co-injected with GL261 and nTh17 survived significantly longer than gTh17 (P < 0.006) and gliomas expressed high level of IFN-γ and TNF-α, low levels of IL-10 and TGF-β. In vitro IL-17 per se did not exert effects on GL261 proliferation; in vivo gliomas grew equally well intracranially in IL-17 deficient and wild-type mice. We further analyzed relationship between Th17 cells and Treg. Treg were significantly higher in splenocytes from glioma-bearing than naïve mice (P = 0.01) and gTh17 produced more IL-10 than IFN-γ (P = 0.002). In vitro depletion of Treg using PC61 in splenocytes from glioma-bearing mice causes increased IL-17/IFN-γ cells (P = 0.007) and decreased IL-17/IL-10 cells (P = 0.03). These results suggest that Th17 polarization may be induced by Treg and that Th17 cells in gliomas modulate tumor growth depending on locally produced cytokines.
authors.affiliation: Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, via Celoria 11, 20133 Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cantini
authors.forename: Federica
authors.initials: F
authors.lastname: Pisati
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mastropietro
authors.forename: Véronique
authors.initials: V
authors.lastname: Frattini
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D002469:Cell Separation; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D016207:Cytokines