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Lymphocyte apoptosis induced by CD95 (APO–1/Fas) ligand–expressing tumor cells — A mechanism of immune evasion?

Nature Medicine volume 2, pages 1361–1366 (1996)Cite this article

Abstract

The CD95 (APO–1/Fas) system is an important mediator of T–cell cytotoxicity. We investigated this system in 22 hepatocellular carcinomas (HCCs) from patients. All HCCs had partially or completely lost the expression of the CD95 receptor constitutively expressed by normal liver cells and might thus evade CD95–mediated killing. We also considered a new mechanism of immune evasion, namely, the active destruction of T–lymphocytes by tumor cells expressing CD95 ligand (CD95L). CD95L messenger RNA and protein could be detected in the HCCs. In coculture experiments, HepG2 hepatoblastoma cells, expressing CD95L mRNA after treatment with cytostatic drugs, killed CD95+ Jurkat lymphocytes. Our data suggest that tumor cells can evade immune attack by down–regulation of the CD95 receptor and killing of lymphocytes through expression of CD95L.

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References

  1. Krammer, P.H., Behrmann, I., Daniel, P., Dhein, D. & Debatin, K.-M. Regulation of apoptosis in the immune system. Curr. Opin. Immunol. 6, 279–289 (1994).

    Article  CAS  Google Scholar 

  2. Apasov, S., Redegeld, F. & Sitkovsky, M. Cell-mediated cytotoxicity: Contact and secreted factors. Curr. Opin. Immunol. 5, 404–410 (1993).

    Article  CAS  Google Scholar 

  3. Lowin, B., Hahne, M., Mattmann, C. & Tschopp, J., T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650–652 (1994).

    Article  CAS  Google Scholar 

  4. Kägi, D. et al Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369, 31–37 (1994).

    Article  Google Scholar 

  5. Kägi, D. et al. Fas and perforin pathways as major mechanisms of T-cell-mediated cytotoxicity. Science 265, 528–530 (1994).

    Article  Google Scholar 

  6. Rouvier, E., Luciani, M.-F. & Golstein, P. Fas involvement in Ca2+-independent T cell-mediated cytotoxicity. J. Exp. Med. 177, 195–200 (1993).

    Article  CAS  Google Scholar 

  7. Gilette-Ferguson, I. & Sidman, C.L. A specific intercellular pathway of apoptotic cell death is defective in the mature peripheral T cells of autoimmune Ipr and gld mice. Eur. J. Immunol 24, 1181–1185 (1994).

    Article  Google Scholar 

  8. Hanabuchi, S. et al. Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. USA 91, 4930–4934 (1994).

    Article  CAS  Google Scholar 

  9. Ju, S.T., Cui, H., Pauka, D.J., Ettinger, R. & Marshak-Rothstein, A. Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc. Natl. Acad. Sci. USA 91, 4185–4189 (1994).

    Article  CAS  Google Scholar 

  10. Stalder, T., Hahn, S. & Erb, P. Fas antigen is the major target molecule for CD4+ T-cell mediated cytotoxicity. Immunology 152. 1127–1133 (1994).

    CAS  Google Scholar 

  11. Vignaux, F. & Golstein, P. Fas-based lymphocyte-mediated cytotoxicity against syngeneic activated lymphocytes: A regulatory pathway? Eur. J. Immunol. 24, 923–927 (1994).

    Article  CAS  Google Scholar 

  12. Leithäuser, F. et al. Constitutive and induced expression of APO-1, a new member of the NGF/TNF receptor superfamily, in normal and neoplastic cells. Lab. Invest. 69, 415–429 (1993).

    PubMed  Google Scholar 

  13. Galle, P.R. et al. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J. Exp. Med. 182, 1223–1230 (1995).

    Article  CAS  Google Scholar 

  14. Ogasawara, J. et al. Lethal effects of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).

    Article  CAS  Google Scholar 

  15. Bellgrau, D. et al. A role for CD95 ligand in preventing graft rejection. Nature 377, 630–6322 (1995).

    Article  CAS  Google Scholar 

  16. Griffith, T.S., Brunner, T., Fletcher, S.M., Green, D.R. & Ferguson, T.A. Fas lig-and-induced apoptosis as a mechanism of immune privilege. Science 17, 1189–1192 (1995).

    Article  Google Scholar 

  17. Badley, A.D. et al. Upregulation of Fas ligand expression by human immunodeficient virus in human macrophages mediates apoptosis of uninfected T lym phocytes. J. Virol. 70, 199–206 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Volkmann, M. et al. P53 overexpression is frequent in European hepatocellular carcinoma and largely independent of the codon 249 hot spot mutation. Oncogene 9, 195–204 (1994).

    CAS  PubMed  Google Scholar 

  19. Peter, M.E. et al. APO-1 (CD95)-dependent and-independent antigen receptor-induced apoptosis in human T and B cell lines. Int. Immunol. 7, 1873–1877 (1995).

    Article  CAS  Google Scholar 

  20. Friesen, C., Herr, I., Krammer, P.H. & Debatin, K.-M. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nature Med. 2, 574–577 (1996).

    Article  CAS  Google Scholar 

  21. Trauth, B.C. et al. Monoclonal antibody-mediated tumor regression by induc tion of apoptosis. Science 245, 301–305 (1989).

    Article  CAS  Google Scholar 

  22. Nicoletti, I., Migliorati, G., Paggliacci, M.C., Grignani, F. & Riccardi, C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J. Immunol. Methods 139, 271–279 (1991).

    Article  CAS  Google Scholar 

  23. Dhein, J. et al. Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J. Immunol. 149, 3166–3173 (1992).

    CAS  PubMed  Google Scholar 

  24. Tanaka, M. et al. Fas ligand in human serum. Nature Med. 2, 317–322 (1996).

    Article  CAS  Google Scholar 

  25. Yagita, H., Seino, K.-I., Kayagaki, N. & Okumura, K. CD95 ligand in graft rejection [letter]. Nature 379, 682 (1996).

    Article  CAS  Google Scholar 

  26. Angerer, L.M. & Angerer, R.C. In situ hybridization to cellular RNA with radio-labeled RNA probes. in In Situ hybridization: A Practical Approach (ed. Wilkinson, D.G.) 15–32 (Oxford Univ. Press, New York, 1992).

    Google Scholar 

  27. Aden, D.P., Fogel, A., Plotkin, S., Damjanov, I. & Knowles, B.B. Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature 282, 615–616 (1979).

    Article  CAS  Google Scholar 

  28. Sellins, K.S. & Cohen, J.J. Gene induction by γ-irradiation leads to DNA frag mentation in lymphocytes. Immunol. 139, 3199–3206 (1987).

    CAS  Google Scholar 

  29. Southern, E.M. Detection of specific sequences among DNA fragments sepa rated by gel electrophoresis. J. Mol. Biol. 98, 503–517 (1975).

    Article  CAS  Google Scholar 

  30. Mariani, S.M., Matiba, B., Bäumler, C. & Krammer, P. Regulation of cell surface APO-1/Fas (CD95) ligand expression by metalloproteases. Eur. J. Immunol. 25, 2303–2307 (1995).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, University Hospital, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Susanne Strand, Martina Müller, Wolfgang Stremmel & Peter R. Galle

  2. Institute of Pathology, Im Neuenheimer Feld 220, Im Neuenheimer Feld 282, 69120, Heidelberg, Germany

    Walter J. Hofmann

  3. Center of Molecular Biology (ZMBH), Im Neuenheimer Feld 282, 69120, Heidelberg, Germany

    Hubert Hug

  4. Department of Surgery, University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Gerd Otto

  5. Department of Developmental Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Dennis Strand

  6. Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Sara M. Mariani & Peter H. Krammer

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  1. Susanne Strand
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Strand, S., Hofmann, W., Hug, H. et al. Lymphocyte apoptosis induced by CD95 (APO–1/Fas) ligand–expressing tumor cells — A mechanism of immune evasion?. Nat Med 2, 1361–1366 (1996). https://doi.org/10.1038/nm1296-1361

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  • DOI: https://doi.org/10.1038/nm1296-1361

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