Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Sep 1;184(3):1075–1082. doi: 10.1084/jem.184.3.1075

The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand

PMCID: PMC2192789  PMID: 9064324

Abstract

Tumors escape immunological rejection by a diversity of mechanisms. In this report, we demonstrate that the colon cancer cell SW620 expresses functional Fas ligand (FasL), the triggering agent of Fas receptor (FasR)-mediated apoptosis within the immune system. FasL mRNA and cell surface FasL were detected in SW620 cells using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. We show that SW620 kills Jurkat T cells in a Fas-mediated manner. FasR-specific antisense oligonucleotide treatment, which transiently inhibited FasR expression, completely protected Jurkat cells from killing by SW620. FasL-specific antisense oligonucleotide treatment of SW620 inhibited its Jurkat-killing activity. FasL has recently been established as a mediator of immune privilege in mouse retina and testis. Our finding that colon cancer cells express functional FasL suggests it may play an analogous role in bestowing immune privilege on human tumors. HT29 and SW620 colon cancer cells were found to express FasR mRNA and cell surface FasR using RT-PCR and immunofluorescence flow cytometry, respectively. However, neither of these cells underwent apoptosis after treatment by the anti-FasR agonistic monoclonal antibody CH11. Our results therefore suggest a Fas counterattack model for immune escape in colon cancer, whereby the cancer cells resist Fas-mediated T cell cytotoxicity but express functional FasL, an apoptotic death signal to which activated T cells are inherently sensitive.

Full Text

The Full Text of this article is available as a PDF (2.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bellgrau D., Gold D., Selawry H., Moore J., Franzusoff A., Duke R. C. A role for CD95 ligand in preventing graft rejection. Nature. 1995 Oct 19;377(6550):630–632. doi: 10.1038/377630a0. [DOI] [PubMed] [Google Scholar]
  3. Bergelson L. D. Gangliosides and antitumor immunity. Clin Investig. 1993 Aug;71(8):590–594. doi: 10.1007/BF00184480. [DOI] [PubMed] [Google Scholar]
  4. Broaddus R. R., Wargovich M. J., Castro G. A. Early stages of 1,2-dimethylhydrazine-induced colon carcinogenesis suppress immune-regulated ion transport of mouse distal colon. Cancer Res. 1994 Nov 15;54(22):5930–5936. [PubMed] [Google Scholar]
  5. Capaccioli S., Di Pasquale G., Mini E., Mazzei T., Quattrone A. Cationic lipids improve antisense oligonucleotide uptake and prevent degradation in cultured cells and in human serum. Biochem Biophys Res Commun. 1993 Dec 15;197(2):818–825. doi: 10.1006/bbrc.1993.2552. [DOI] [PubMed] [Google Scholar]
  6. Cascino I., Fiucci G., Papoff G., Ruberti G. Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol. 1995 Mar 15;154(6):2706–2713. [PubMed] [Google Scholar]
  7. Cheng J., Zhou T., Liu C., Shapiro J. P., Brauer M. J., Kiefer M. C., Barr P. J., Mountz J. D. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 1994 Mar 25;263(5154):1759–1762. doi: 10.1126/science.7510905. [DOI] [PubMed] [Google Scholar]
  8. Copeland K. F., Haaksma A. G., Goudsmit J., Krammer P. H., Heeney J. L. Inhibition of apoptosis in T cells expressing human T cell leukemia virus type I Tax. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1259–1268. doi: 10.1089/aid.1994.10.1259. [DOI] [PubMed] [Google Scholar]
  9. Daniel P. T., Krammer P. H. Activation induces sensitivity toward APO-1 (CD95)-mediated apoptosis in human B cells. J Immunol. 1994 Jun 15;152(12):5624–5632. [PubMed] [Google Scholar]
  10. Debatin K. M., Krammer P. H. Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program. Leukemia. 1995 May;9(5):815–820. [PubMed] [Google Scholar]
  11. Degols G., Leonetti J. P., Mechti N., Lebleu B. Antiproliferative effects of antisense oligonucleotides directed to the RNA of c-myc oncogene. Nucleic Acids Res. 1991 Feb 25;19(4):945–948. doi: 10.1093/nar/19.4.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fisher G. H., Rosenberg F. J., Straus S. E., Dale J. K., Middleton L. A., Lin A. Y., Strober W., Lenardo M. J., Puck J. M. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995 Jun 16;81(6):935–946. doi: 10.1016/0092-8674(95)90013-6. [DOI] [PubMed] [Google Scholar]
  13. Gibellini D., Caputo A., Celeghini C., Bassini A., La Placa M., Capitani S., Zauli G. Tat-expressing Jurkat cells show an increased resistance to different apoptotic stimuli, including acute human immunodeficiency virus-type 1 (HIV-1) infection. Br J Haematol. 1995 Jan;89(1):24–33. doi: 10.1111/j.1365-2141.1995.tb08915.x. [DOI] [PubMed] [Google Scholar]
  14. 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. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  15. Itoh N., Tsujimoto Y., Nagata S. Effect of bcl-2 on Fas antigen-mediated cell death. J Immunol. 1993 Jul 15;151(2):621–627. [PubMed] [Google Scholar]
  16. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  17. Ju S. T., Cui H., Panka 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 U S A. 1994 May 10;91(10):4185–4189. doi: 10.1073/pnas.91.10.4185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jättelä M., Benedict M., Tewari M., Shayman J. A., Dixit V. M. Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells. Oncogene. 1995 Jun 15;10(12):2297–2305. [PubMed] [Google Scholar]
  19. Li R., Gage D., Ladisch S. Biosynthesis and shedding of murine lymphoma gangliosides. Biochim Biophys Acta. 1993 Nov 3;1170(3):283–290. doi: 10.1016/0005-2760(93)90011-w. [DOI] [PubMed] [Google Scholar]
  20. Matsue H., Kobayashi H., Hosokawa T., Akitaya T., Ohkawara A. Keratinocytes constitutively express the Fas antigen that mediates apoptosis in IFN gamma-treated cultured keratinocytes. Arch Dermatol Res. 1995;287(3-4):315–320. doi: 10.1007/BF01105085. [DOI] [PubMed] [Google Scholar]
  21. Matzinger P. The JAM test. A simple assay for DNA fragmentation and cell death. J Immunol Methods. 1991 Dec 15;145(1-2):185–192. doi: 10.1016/0022-1759(91)90325-a. [DOI] [PubMed] [Google Scholar]
  22. Mountz J. D., Wu J., Cheng J., Zhou T. Autoimmune disease. A problem of defective apoptosis. Arthritis Rheum. 1994 Oct;37(10):1415–1420. doi: 10.1002/art.1780371002. [DOI] [PubMed] [Google Scholar]
  23. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  24. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  25. O'Mahony A. M., O'Sullivan G. C., O'Connell J., Cotter T. G., Collins J. K. An immune suppressive factor derived from esophageal squamous carcinoma induces apoptosis in normal and transformed cells of lymphoid lineage. J Immunol. 1993 Nov 1;151(9):4847–4856. [PubMed] [Google Scholar]
  26. Owen-Schaub L. B., Radinsky R., Kruzel E., Berry K., Yonehara S. Anti-Fas on nonhematopoietic tumors: levels of Fas/APO-1 and bcl-2 are not predictive of biological responsiveness. Cancer Res. 1994 Mar 15;54(6):1580–1586. [PubMed] [Google Scholar]
  27. Owen-Schaub L. B., Zhang W., Cusack J. C., Angelo L. S., Santee S. M., Fujiwara T., Roth J. A., Deisseroth A. B., Zhang W. W., Kruzel E. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 1995 Jun;15(6):3032–3040. doi: 10.1128/mcb.15.6.3032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Quirk S. M., Cowan R. G., Joshi S. G., Henrikson K. P. Fas antigen-mediated apoptosis in human granulosa/luteal cells. Biol Reprod. 1995 Feb;52(2):279–287. doi: 10.1095/biolreprod52.2.279. [DOI] [PubMed] [Google Scholar]
  29. Rieux-Laucat F., Le Deist F., Hivroz C., Roberts I. A., Debatin K. M., Fischer A., de Villartay J. P. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995 Jun 2;268(5215):1347–1349. doi: 10.1126/science.7539157. [DOI] [PubMed] [Google Scholar]
  30. Sayama K., Yonehara S., Watanabe Y., Miki Y. Expression of Fas antigen on keratinocytes in vivo and induction of apoptosis in cultured keratinocytes. J Invest Dermatol. 1994 Sep;103(3):330–334. doi: 10.1111/1523-1747.ep12394858. [DOI] [PubMed] [Google Scholar]
  31. Shima Y., Nishimoto N., Ogata A., Fujii Y., Yoshizaki K., Kishimoto T. Myeloma cells express Fas antigen/APO-1 (CD95) but only some are sensitive to anti-Fas antibody resulting in apoptosis. Blood. 1995 Feb 1;85(3):757–764. [PubMed] [Google Scholar]
  32. Tanaka M., Suda T., Haze K., Nakamura N., Sato K., Kimura F., Motoyoshi K., Mizuki M., Tagawa S., Ohga S. Fas ligand in human serum. Nat Med. 1996 Mar;2(3):317–322. doi: 10.1038/nm0396-317. [DOI] [PubMed] [Google Scholar]
  33. Weller M., Frei K., Groscurth P., Krammer P. H., Yonekawa Y., Fontana A. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest. 1994 Sep;94(3):954–964. doi: 10.1172/JCI117462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Weller M., Malipiero U., Aguzzi A., Reed J. C., Fontana A. Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest. 1995 Jun;95(6):2633–2643. doi: 10.1172/JCI117965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weller M., Malipiero U., Rensing-Ehl A., Barr P. J., Fontana A. Fas/APO-1 gene transfer for human malignant glioma. Cancer Res. 1995 Jul 1;55(13):2936–2944. [PubMed] [Google Scholar]
  36. Wright S. C., Zhong J., Larrick J. W. Inhibition of apoptosis as a mechanism of tumor promotion. FASEB J. 1994 Jun;8(9):654–660. doi: 10.1096/fasebj.8.9.8005393. [DOI] [PubMed] [Google Scholar]
  37. Wright S. C., Zhong J., Zheng H., Larrick J. W. Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J. 1993 Aug;7(11):1045–1051. [PubMed] [Google Scholar]
  38. Yagita M., Seppo A., Renkonen O., Saksela E. Deacetylase activity of human tumor cells producing immunosuppressive aminosugars: its possible role in resistance to cell-mediated cytotoxicity. Cancer Res. 1993 Dec 1;53(23):5600–5604. [PubMed] [Google Scholar]
  39. Yonehara S., Nishimura Y., Kishil S., Yonehara M., Takazawa K., Tamatani T., Ishii A. Involvement of apoptosis antigen Fas in clonal deletion of human thymocytes. Int Immunol. 1994 Dec;6(12):1849–1856. doi: 10.1093/intimm/6.12.1849. [DOI] [PubMed] [Google Scholar]
  40. Yoshino T., Kondo E., Cao L., Takahashi K., Hayashi K., Nomura S., Akagi T. Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes. Blood. 1994 Apr 1;83(7):1856–1861. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES