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Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells

Nature Medicine volume 10, pages 48–54 (2004)Cite this article

A Corrigendum to this article was published on 01 February 2004

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.

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Figure 1: Blocking Stat-3 in tumor cells increases proinflammatory cytokine and chemokine expression.
Figure 2: Constitutive Stat-3 activity inhibits cytokine and chemokine gene expression.
Figure 3: Blocking Stat-3 in tumor cells stimulates macrophages and neutrophils.
Figure 4: Stat-3-interrupted tumor cells activated dendritic cells and naive antigen-specific T cells.
Figure 5: Stat-3 signaling induces expression of factors that inhibit dendritic cell maturation.
Figure 6: Stat-3 signaling mediates inhibition of dendritic cell maturation.

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Acknowledgements

We thank S. Akira and K. Takeda for Stat3flox mice, D. Link for the Stat-3C and Stat-3D retrovirus–producing cell lines, J. Bromberg for the Stat-3C plasmid and H. von Boehmer for CD4+ TCR transgenic mice. This work is supported by US National Institutes of Health grants, by the Dr. Tsai-fan Yu Cancer Research Endowment and by gifts from Mrs. Dorothy Needle, William and Betty Topercer, Jack Goldsmith, the Janey Fund and the Seraph Foundation.

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  1. Tianhong Wang, Guilian Niu, Marcin Kortylewski and Lyudmila Burdelya: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Tianhong Wang & Drew Pardoll

  2. Department of Interdisciplinary Oncology, Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Guilian Niu, Marcin Kortylewski, Lyudmila Burdelya, Raka Bhattacharya, Dmitry Gabrilovich & Hua Yu

  3. Department of Interdisciplinary Oncology, Clinical Investigations Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Kenneth Shain, Richard Heller, Domenico Coppola & William Dalton

  4. Department of Interdisciplinary Oncology, Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, 33612, Florida, USA

    Shumin Zhang & Richard Jove

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Correspondence to Drew Pardoll or Hua Yu.

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Wang, T., Niu, G., Kortylewski, M. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10, 48–54 (2004). https://doi.org/10.1038/nm976

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