Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape

Based on early studies, it was hypothesized that expression of Fas ligand (FasL) by tumor cells enabled them to counterattack the immune system, and that transplant rejection could be prevented by expressing FasL on transplanted organs. More recent studies have indicated that the notion of FasL as a mediator of immune privilege needed to be reconsidered, and taught a valuable lesson about making broad conclusions based on small amounts of data.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FasL-induced T cell death.

References

  1. O'Connell, J., Bennett, M.W., O'Sullivan, G.C., Collins, J.K. & Shanahan, F. Fas counter-attack—the best form of tumor defense? Nature Med. 5, 267–268 (1999).

    Article  CAS  Google Scholar 

  2. Vaux, D.L. Immunology. Ways around rejection. Nature 377, 576–577 (1995); retraction: 394, 133 (1998).

    Article  CAS  Google Scholar 

  3. Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A. & Duke, R.C. A role for CD95 ligand in preventing graft rejection. Nature 377, 630–632 (1995); erratum: 394, 133 (1998).

    Article  CAS  Google Scholar 

  4. Lau, H.T., Yu, M., Fontana, A. & Stoeckert, C.J.J. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273, 109–112 (1996).

    Article  CAS  Google Scholar 

  5. Griffith, T.S., Brunner, T., Fletcher, S.M., Green, D.R. & Ferguson, T.A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).

    Article  CAS  Google Scholar 

  6. Yagita, H., Seino, K., Kayagaki, N. & Okumura, K. CD95 ligand in graft rejection. Nature 379, 682(1996).

    Article  CAS  Google Scholar 

  7. Hahne, M., Rimoldi, D., Schroter, M., et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274, 1363–1366 (1996).

    Article  CAS  Google Scholar 

  8. Allison, J., Georgiou, H.M., Strasser, A. & Vaux, D.L. Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc. Natl. Acad. Sci USA 94, 3943–3947 (1997).

    Article  CAS  Google Scholar 

  9. Kang, S.M. et al. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nature Med. 3, 738–743 (1997).

    Article  CAS  Google Scholar 

  10. Kang, S.M., Lin, Z., Ascher, N.L. & Stock, P.G. Fas ligand expression on islets as well as multiple cell lines results in accelerated neutrophilic rejection. Transplant. Proc. 30, 538 (1998).

    Article  CAS  Google Scholar 

  11. Kang, S.M., Hoffmann, A., Le, D., Springer, M.L., Stock, P.G. & Blau, H.M. Immune response and myoblasts that express Fas ligand. Science 278, 1322–1324 (1997).

    Article  CAS  Google Scholar 

  12. Seino, K. et al. Attempts to reveal the mechanism of CD95-ligand-mediated inflammation. Transplant. Proc. 31, 1942–1943 (1999).

    Article  CAS  Google Scholar 

  13. Seino, K. et al. Chemotactic activity of soluble Fas ligand against phagocytes. J.Immunol. 161, 4484–4488 (1998).

    CAS  PubMed  Google Scholar 

  14. Seino, K., Kayagaki, N., Fukao, K., Okumura, K. & Yagita, H. Rejection of Fas ligand-expressing grafts. Transplant. Proc. 29, 1092–1093 (1997).

    Article  CAS  Google Scholar 

  15. Seino, K., Kayagaki, N., Bashuda, H., Okumura, K. & Yagita, H. Contribution of Fas ligand to cardiac allograft rejection. Int. Immunol. 8, 1347–1354 (1996).

    Article  CAS  Google Scholar 

  16. Chappell, D.B., Zaks, T.Z., Rosenberg, S.A. & Restifo, N.P. Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res. 59, 59–62 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Arai, H., Gordon, D., Nabel, E.G. & Nabel, G.J. Gene transfer of Fas ligand induces tumor regression in vivo. Proc. Natl. Acad. Sci. USA 94, 13862–13867 (1997).

    Article  CAS  Google Scholar 

  18. Hohlbaum, A.M., Moe, S. & Rothstein, A.M. Opposing Effects of Transmembrane and Soluble Fas Ligand Expression on Inflammation and Tumor Cell Survival. J. Exp. Med. 191, 1209–1220 (2000).

    Article  CAS  Google Scholar 

  19. Muzio, M. et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death—inducing signaling complex. Cell 85, 817–827 (1996).

    Article  CAS  Google Scholar 

  20. Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).

    Article  CAS  Google Scholar 

  21. Ray, C.A. et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1β converting enzyme. Cell 69, 597–604 (1992).

    Article  CAS  Google Scholar 

  22. Smith, D., Sieg, S. & Kaplan, D. Technical note: Aberrant detection of cell surface Fas ligand with anti-peptide antibodies. J. Immunol. 160, 4159–4160 (1998).

    CAS  PubMed  Google Scholar 

  23. Gastman, B.R. et al. Fas ligand is expressed on human squamous cell carcinomas of the head and neck, and it promotes apoptosis of T lymphocytes. Cancer Res. 59, 5356–5364 (1999).

    CAS  PubMed  Google Scholar 

  24. De Maria, R. et al. Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation. J. Clin. Invest. 97, 316–322 (1996).

    Article  CAS  Google Scholar 

  25. Fiedler, P., Schaetzlein, C.E. & Eibel, H. Constitutive expression of FasL in thyrocytes. Science 279, 2015a(1998).

    Article  Google Scholar 

  26. Ekmekcioglu, S. et al. Differential increase of Fas ligand expression on metastatic and thin or thick primary melanoma cells compared with interleukin-10. Melanoma Res. 9, 261–272 (1999).

    Article  CAS  Google Scholar 

  27. Henkart, P.A., Williams, M.S., Zacharchuk, C.M. & Sarin, A. Do CTL kill target cells by inducing apoptosis? Semin. Immunol. 9, 135–144 (1997).

    Article  CAS  Google Scholar 

  28. Lenardo, M. et al. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).

    Article  CAS  Google Scholar 

  29. Zaks, T.Z., Chappell, D.B., Rosenberg, S.A. & Restifo, N.P. Fas-mediated suicide of tumor-reactive T cells following activation by specific tumor: selective rescue by caspase inhibition. J. Immunol. 162, 3273–3279 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chappell, D.B. & Restifo, N.P. T cell-tumor cell: a fatal interaction? Cancer Immunol. Immunother. 47, 65–71 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The author thanks D. Chappell, T. Zaks, P. Henkart, S. Rosenberg and M. Lenardo for help with experiments and ideas described above.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Restifo, N. Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med 6, 493–495 (2000). https://doi.org/10.1038/74955

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/74955

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing