Nature Medicine10, 48 - 54 (2004)
Published online: 21 December 2003; | doi:10.1038/nm976
There is a Corrigendum (February 2004) associated with this Article.
Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells
Tianhong Wang1, 5, Guilian Niu2, 5, Marcin Kortylewski2, 5, Lyudmila Burdelya2, 5, Kenneth Shain3, Shumin Zhang4, Raka Bhattacharya2, Dmitry Gabrilovich2, Richard Heller3, Domenico Coppola3, William Dalton3, Richard Jove4, Drew Pardoll1
& Hua Yu2
1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
2
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
3
Clinical Investigations Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
4
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
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.
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