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.

  • Original Article
  • Published:

Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity

Cancer Gene Therapy volume 10, pages 134–140 (2003)Cite this article

Abstract

The interaction between Fas and Fas ligand (FasL) is involved in the apoptotic death of a number of cells including lymphocytes. Forced expression of FasL in tumors can induce apoptosis of infiltrating Fas-positive T cells; accordingly, tumors can survive in the milieu of systemic immune responses. However, FasL-expressing murine lung carcinoma (A11) and melanoma (B16) cells did not develop subcutaneous tumors and FasL-expressing A11 (A11/FasL) cells produced few spontaneous lung metastatic foci in syngeneic mice. The mice that rejected A11/FasL cells were resistant to subsequent challenge of parent A11 but not irrelevant B16 cells. Vaccination of mice with UV-treated A11/FasL, but not UV-treated A11 cells, however, augmented the growth rate of A11 but not B16 tumors, both of which were subsequently inoculated. The number of lung metastatic foci of A11 cells was also increased in the mice that received UV-treated A11/FasL but not UV-treated A11 cells. Intraperitoneal injection of UV-treated A11/FasL cells resulted in the production of larger amounts of immunosuppressive TGF-β in peritoneal exudate than that of UV-treated A11 cells. Expression of the CD80 costimulatory molecule in tissues where UV-treated A11/FasL cells were inoculated was lower than the expression at an untreated A11/FasL–injected site. Our results indicated that apoptotic FasL-expressing tumor cells could impair host immune responses against the tumors, in contrast to potent antitumor immunity generated by viable FasL-expressing tumors.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Suda T, Takahashi T, Goldstein P, et al. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169–1178.

    Article  CAS  Google Scholar 

  2. Nagata S . Fas and Fas ligand: a death factor and its receptor. Adv Immunol. 1994;57:129–144.

    Article  CAS  Google Scholar 

  3. Alderson MR, Tough TW, Davis-Smith T, et al. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995;181:71–77.

    Article  CAS  Google Scholar 

  4. Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81:935–946.

    Article  CAS  Google Scholar 

  5. Takahashi T, Tanaka M, Brannan CI, et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994;76:969–976.

    Article  CAS  Google Scholar 

  6. Kagi D, Vignaux F, Ledermann B, et al. Fas and perforin pathways as major mechanisms of T cell–mediated cytotoxicity. Science. 1994;265:528–530.

    Article  CAS  Google Scholar 

  7. Bellgrau D, Gold D, Selawry H, et al. A role for CD95 ligand in preventing graft rejection. Nature. 1995;377:630–632.

    Article  CAS  Google Scholar 

  8. Griffith TS, Brunner T, Fletcher SM, et al. Fas ligand–induced apoptosis as a mechanism of immune privilege. Science. 1995;270:1189–1192.

    Article  CAS  Google Scholar 

  9. Strand S, Hofmann WJ, Hug H, et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells — a mechanism of immune evasion?. Nat Med. 1996;2:1361–1366.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. O'Connell J, O'Sullivan GC, Collins JK, et al. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med. 1996;184:1075–1082.

    Article  CAS  Google Scholar 

  12. Seino K, Kayagaki N, Okumura K, et al. Antitumor effect of locally produced CD95 ligand. Nat Med. 1997;3:165–170.

    Article  CAS  Google Scholar 

  13. Arai H, Gordon D, Nabel EG, et al. Gene transfer of Fas ligand induces tumor regression in vivo. Proc Natl Acad Sci USA. 1997;94:13862–13867.

    Article  CAS  Google Scholar 

  14. Drozdzik M, Qian C, Lasarte JJ, et al. Antitumor effect of allogenic fibroblasts engineered to express Fas ligand (FasL). Gene Ther. 1998;5:1622–1630.

    Article  CAS  Google Scholar 

  15. Restifo NP . Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med. 2000;6:493–495.

    Article  CAS  Google Scholar 

  16. O'Connell J, Houston A, Bennett MW, et al. Immune privilege or inflammation? Insight into the Fas ligand enigma. Nat Med. 2001;7:271–274.

    Article  CAS  Google Scholar 

  17. Chen J-J, Sun Y, Nabel GJ . Regulation of the proinflammatory effects of Fas ligand (CD95L). Science. 1998;282:1714–1717.

    Article  CAS  Google Scholar 

  18. Takasu M, Tada J, Wang JO, et al. Resistance to apoptosis induced by microenvironmental stresses is correlated with metastatic potential in Lewis lung carcinoma. Clin Exp Metastasis. 1999;17:409–416.

    Article  CAS  Google Scholar 

  19. Wang J, Koizumi T, Watanabe T . Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in lyn-deficient mice. J Exp Med. 1996;184:831–838.

    Article  CAS  Google Scholar 

  20. Takenaga K . Characterization of low- and high-metastatic clones isolated from a Lewis lung carcinoma. Jpn J Cancer Res (Gann). 1984;75:61–71.

    CAS  Google Scholar 

  21. Sauter B, Albert ML, Francisco L, et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med. 2000;191:423–433.

    Article  CAS  Google Scholar 

  22. Melcher A, Todryk S, Hardwick N, et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med. 1998;4:581–587.

    Article  CAS  Google Scholar 

  23. Voll RE, Herrmann M, Roth EA, et al. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–351.

    Article  CAS  Google Scholar 

  24. Fadok VA, Bratton DL, Konowal A, et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J Clin Invest. 1998;101:890–898.

    Article  CAS  Google Scholar 

  25. Ronchetti A, Rovere P, Iezzi G, et al. Immunogenicity of apoptotic cells in vivo: role of antigen load, antigen-presenting cells, and cytokines. J Immunol. 1999;163:130–136.

    CAS  PubMed  Google Scholar 

  26. Heath WR, Kurts C, Miller JFAP, et al. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J Exp Med. 1998;187:1549–1553.

    Article  CAS  Google Scholar 

  27. Geissmann F, Revy P, Regnault A, et al. TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol. 1999;162:4567–4575.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science and a grant-in-aid for scientific research on priority areas from the Minister of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

  1. Division of Pathology, Chiba Cancer Center Research Institute, Chuo-ku, Chiba, Japan

    Yuji Tada, Jiyang O-Wang, Akihiko Wada, Shigeru Sakiyama & Masatoshi Tagawa

  2. Department of Respirology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan

    Yuji Tada, Akihiko Wada, Yuichi Takiguchi, Koichiro Tatsumi & Takayuki Kuriyama

Authors
  1. Yuji Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiyang O-Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihiko Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuichi Takiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koichiro Tatsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takayuki Kuriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shigeru Sakiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masatoshi Tagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masatoshi Tagawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tada, Y., O-Wang, J., Wada, A. et al. Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity. Cancer Gene Ther 10, 134–140 (2003). https://doi.org/10.1038/sj.cgt.7700545

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700545

Keywords

This article is cited by

Search

Advanced search

Quick links