TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis

Nele Müller-Hermelink, Heidi Braumüller, Bernd Pichler, Thomas Wieder, Reinhard Mailhammer, Katrin Schaak, Kamran Ghoreschi, Amir Yazdi, Roland Haubner, Christian A Sander, Ralph Mocikat, Markus Schwaiger, Irmgard Förster, Ralph Huss, Wolfgang A Weber, Manfred Kneilling, Martin Röcken

Research output: Contribution to journalArticlepeer-review


Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.

Original languageEnglish
Pages (from-to)507-18
Number of pages12
JournalCancer Cell
Issue number6
Publication statusPublished - Jun 2008


  • Animals
  • Antigens, Viral, Tumor
  • Blood Glucose
  • CD4-Positive T-Lymphocytes
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • GTPase-Activating Proteins
  • Immunotherapy
  • Insulinoma
  • Integrin alphaVbeta3
  • Interferon-gamma
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Pathologic
  • Pancreatic Neoplasms
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction
  • Th1 Cells
  • Time Factors
  • Whole-Body Irradiation


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