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

doi:10.1016/j.ccr.2008.04.001

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

Cancer Cell. 2008 Jun;13(6):507-18. doi: 10.1016/j.ccr.2008.04.001.

Authors

Nele Müller-Hermelink¹, 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

Affiliation

¹ Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.

PMID: 18538734
DOI: 10.1016/j.ccr.2008.04.001

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Viral, Tumor / genetics
Antigens, Viral, Tumor / metabolism
Blood Glucose / metabolism
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / pathology
CD4-Positive T-Lymphocytes / transplantation
Cell Movement
Cell Proliferation*
Cell Survival
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / immunology*
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Cells, Cultured
GTPase-Activating Proteins / genetics
GTPase-Activating Proteins / metabolism
Immunotherapy / methods
Insulinoma / blood supply
Insulinoma / genetics
Insulinoma / immunology*
Insulinoma / metabolism
Insulinoma / pathology
Insulinoma / therapy
Integrin alphaVbeta3 / metabolism
Interferon-gamma / metabolism*
Mice
Mice, Inbred C3H
Mice, Knockout
Mice, Transgenic
Neovascularization, Pathologic / immunology
Neovascularization, Pathologic / pathology
Pancreatic Neoplasms / blood supply
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / immunology*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy
Receptors, Tumor Necrosis Factor, Type I / deficiency
Receptors, Tumor Necrosis Factor, Type I / genetics
Receptors, Tumor Necrosis Factor, Type I / metabolism*
Signal Transduction*
Th1 Cells / immunology
Th1 Cells / pathology
Time Factors
Whole-Body Irradiation

Substances

Antigens, Viral, Tumor
Blood Glucose
GTPase-Activating Proteins
Integrin alphaVbeta3
Ralbp1 protein, mouse
Receptors, Tumor Necrosis Factor, Type I
Tnfrsf1a protein, mouse
Interferon-gamma