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Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains

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Abstract

Inbred rat strains BDIX and BDIV are constitutionally susceptible and resistant, respectively, to the development of malignant peripheral nerve sheath tumors (MPNST) induced by neonatal exposure to N-ethyl-N-nitrosourea (EtNU). They represent a model system for analysis of molecular and cellular processes underlying differential cancer susceptibility. A point mutation in the Neu/ErbB-2 gene is an early marker of Schwann precursor cells at high risk of malignant conversion and is diagnostic of the resulting MPNST predominantly developing in the trigeminal nerves. Initially considerable amounts of Neu/ErbB-2-mutant cells arise in nerve tissue of both rat strains subsequently disappearing in resistant BDIV rats, but persisting and giving rise to MPNST in susceptible BDIX animals. An almost identical cellular immune response—sequentially involving macrophages, T helper- and cytotoxic T lymphocytes—is mounted in the trigeminal nerves of EtNU-treated rats of both strains. In this study, T cell maturation was prevented by neonatal thymectomy following EtNU-exposure. While resistance against MPNST development significantly decreased in BDIV rats MPNST incidence and survival time remained unaltered in thymectomized BDIX rats. Contrary to euthymic animals a number of both thymectomized BDIV and BDIX rats developed MPNST lacking the Neu/ErbB-2-mutation. This suggests that Schwann cells initiated by other genetic alterations can progress to full malignancy in immune-compromised rats only. T cell-dependent resistance against tumorigenesis originating from non-Neu/ErbB-2-mutant Schwann precursors might thus be shared by both strains while BDIV T lymphocytes additionally prevent the development of Neu/ErbB-2-mutant MPNST. Rat strain-specific differences in the interaction of T lymphocytes with (pre)malignant Neu-mutant cells may thus critically contribute to susceptibility and resistance towards EtNU-induced MPNST development.

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Acknowledgments

The authors wish to thank Thomas Haberland and Michael Oepp at the Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, for expert assistance with animal husbandry and surgical procedures. J. A. M. M was the recipient of a scholarship from the Graduate Program of the Deutsche Forschungsgemeinschaft, Bonn “Pathogenesis of nervous system diseases” which also provided funds for this work together with the Bonfor-Program (University of Bonn Research Council).

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  1. Bernd U. Koelsch & Andrea Kindler-Röhrborn

    Present address: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

Authors and Affiliations

  1. Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Judith A. M. Marx, Bernd U. Koelsch, Torsten Pietsch & Andrea Kindler-Röhrborn

  2. Department of General, Visceral and Thoracic Surgery, St. Marienhospital, Nassauerstr. 13-19, 59065, Hamm, Germany

    Ansgar J. Röhrborn

  3. Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Christine Fischer

  4. Institute of Virology and Immunobiology, University of Würzburg, Versbacher Str. 7, 97078, Würzburg, Germany

    Thomas Herrmann

  5. Institute of Cell Biology (Cancer Research), University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Manfred F. Rajewsky

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  1. Judith A. M. Marx
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Correspondence to Andrea Kindler-Röhrborn.

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Marx, J.A.M., Röhrborn, A.J., Koelsch, B.U. et al. Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains. Cancer Immunol Immunother 58, 1287–1295 (2009). https://doi.org/10.1007/s00262-008-0641-z

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  • DOI: https://doi.org/10.1007/s00262-008-0641-z

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