gms | German Medical Science

128. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

03.05. - 06.05.2011, München

Immune escape in colorectal carcinoma: role of the IFN-gamma pathway

Meeting Abstract

  • Michael Stürzl - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Christine Hohenadl - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Karoline Lipnik - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Matthias Ocker - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Elisabeth Naschberger - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Vera Schellerer - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Roland Croner - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen
  • Nathalie Britzen-Laurent - Chirurgische Klinik der Universität Erlangen, Molekulare und Experimentelle Chirurgie, Erlangen

Deutsche Gesellschaft für Chirurgie. 128. Kongress der Deutschen Gesellschaft für Chirurgie. München, 03.-06.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11dgch333

DOI: 10.3205/11dgch333, URN: urn:nbn:de:0183-11dgch3331

Published: May 20, 2011

© 2011 Stürzl et al.
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Outline

Text

Introduction: The presence of a Th1 adaptive immune response has been associated with improved clinical outcome and survival of patients with colorectal carcinoma (CRC). The Th1 adaptive immune response is mediated by IFN-γ. Using guanylate-binding protein 1 (GBP-1) as a well established marker for IFN-γ-responsiveness, we observed that GBP-1 expression in CRC tissues with a TH1 immune reaction is restricted to the desmoplastic stroma and only rarely observed in the tumor cells. In contrast, normal colonic epithelial cells produced high amounts of GBP-1 in presence of IFN-γ, suggesting that CRC tumor cells may have lost their responsiveness to IFN-γ.

Materials and methods: The expression of IFN-γ target proteins (GBP-1, MxA and caspase-1) or members of the IFN-γ pathway (IFNγRα, Stat-1, JAK-1, IRF-1) was investigated in 6 different CRC cell lines by western-blot. The IFN-γ-induced apoptosis was evaluated in parallel by flow cytometry. Ectopic over-expression of GBP-1 and subsequent xenotransplant analyses were used in order to determine the impact of GBP-1 expression on tumorigenicity of CRC cell lines.

Results: We showed that the induction of GBP-1 by IFN-γ was absent in 3 of 6 CRC cell lines, as well as the induction of caspase-1 or MxA. In these cell lines, the loss of expression of IFN-γ target proteins correlated with an absence of apoptosis induction by IFN-γ. In two cell lines, the loss of IFN-γ responsiveness was associated with the absence of the alpha chain of the IFN-γ receptor. Re-introduction of GBP-1 by ectopic over-expression in one of the negative cell lines significantly reduced the tumorigenicity in xenotransplant analyses.

Conclusion: Our data suggest that the ability to respond to IFN-γ can be defective in CRC cells. Molecular analyses of the integrity of the IFN-γ response pathway may predict the response of patients to a Th1 immune response and may have important repercussions on patient recruitment for immune-based therapy in CRC.