Ablation of T cell immunity differentially influences tumor risk in inbred BD rat strains |
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Authors: | Judith A. M. Marx Ansgar J. Röhrborn Bernd U. Koelsch Christine Fischer Thomas Herrmann Torsten Pietsch Manfred F. Rajewsky Andrea Kindler-Röhrborn |
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Affiliation: | 1.Department of Neuropathology,University of Bonn Medical Center,Bonn,Germany;2.Institute of Pathology and Neuropathology,University Hospital of Essen, University of Duisburg-Essen,Essen,Germany;3.Department of General, Visceral and Thoracic Surgery,St. Marienhospital,Hamm,Germany;4.Institute of Human Genetics,University of Heidelberg,Heidelberg,Germany;5.Institute of Virology and Immunobiology,University of Würzburg,Würzburg,Germany;6.Institute of Cell Biology (Cancer Research),University Hospital of Essen, University of Duisburg-Essen,Essen,Germany |
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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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Keywords: | Tumor immunosurveillance Malignant schwannoma Rodent Cancer risk Adaptive immunity |
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