title: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells.
abstract: Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Wang
authors.forename: Guilian
authors.initials: G
authors.lastname: Niu
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Burdelya
authors.forename: Kenneth
authors.initials: K
authors.lastname: Shain
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Raka
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gabrilovich
authors.forename: Richard
authors.initials: R
authors.lastname: Heller
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: William
authors.initials: W
authors.lastname: Dalton
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators