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.
References
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).
Vaux, D.L. Immunology. Ways around rejection. Nature 377, 576–577 (1995); retraction: 394, 133 (1998).
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).
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).
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).
Yagita, H., Seino, K., Kayagaki, N. & Okumura, K. CD95 ligand in graft rejection. Nature 379, 682(1996).
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).
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).
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).
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).
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).
Seino, K. et al. Attempts to reveal the mechanism of CD95-ligand-mediated inflammation. Transplant. Proc. 31, 1942–1943 (1999).
Seino, K. et al. Chemotactic activity of soluble Fas ligand against phagocytes. J.Immunol. 161, 4484–4488 (1998).
Seino, K., Kayagaki, N., Fukao, K., Okumura, K. & Yagita, H. Rejection of Fas ligand-expressing grafts. Transplant. Proc. 29, 1092–1093 (1997).
Seino, K., Kayagaki, N., Bashuda, H., Okumura, K. & Yagita, H. Contribution of Fas ligand to cardiac allograft rejection. Int. Immunol. 8, 1347–1354 (1996).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Fiedler, P., Schaetzlein, C.E. & Eibel, H. Constitutive expression of FasL in thyrocytes. Science 279, 2015a(1998).
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).
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).
Lenardo, M. et al. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).
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).
Chappell, D.B. & Restifo, N.P. T cell-tumor cell: a fatal interaction? Cancer Immunol. Immunother. 47, 65–71 (1998).
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
Rights 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
Issue Date:
DOI: https://doi.org/10.1038/74955
- Springer Nature America, Inc.
This article is cited by
-
Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism
Cancer Immunology, Immunotherapy (2019)
-
Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes
Nature Communications (2017)
-
Fas/Fas Ligand Mediates Keratinocyte Death in Sunitinib-Induced Hand-Foot Skin Reaction
Journal of Investigative Dermatology (2014)
-
Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors
Nature Medicine (2014)
-
Inflammation, Apoptosis, and Necrosis Induced by Neoadjuvant Fas Ligand Gene Therapy Improves Survival of Dogs With Spontaneous Bone Cancer
Molecular Therapy (2012)