Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells.
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.
Wang
Tianhong
T
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Niu
Guilian
G
Kortylewski
Marcin
M
Burdelya
Lyudmila
L
Shain
Kenneth
K
Zhang
Shumin
S
Bhattacharya
Raka
R
Gabrilovich
Dmitry
D
Heller
Richard
R
Coppola
Domenico
D
Dalton
William
W
Jove
Richard
R
Pardoll
Drew
D
Yu
Hua
H
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*
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators