Antitumor effect of locally produced CD95 ligand

Nature Medicine volume 3, pages165–170(1997)Cite this article

Abstract

Activation of the cell-surface antigen CD95 induces apoptosis of CD95-bearing tumor cells. In this study, we investigated the antitumor effect of locally produced CD95 ligand (CD95L) on CD95-negative tumor cells in vivo. Introduction of CD95L cDNA into murine tumor cells did not affect growth in vitro but caused rejection in vivo. Neutrophils were primarily responsible for this rejection. A CD8+ T cell-mediated protective immunity against subsequent challenge with parental tumor cells was also elicited. These results provide evidence for the potential utility of CD95L in tumor eradication and also reveal a proinflammatory function of CD95L.

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References

  1. 1

    Havell, E.A., Fiers, W. & North, R.J. The antitumor function of tumor necrosis factor (TNF). J. Exp. Med. 167, 1067–1085 (1988).

    CAS  Article  Google Scholar 

  2. 2

    Beutler, B. & Cerami, A. The biology of cachectin/TNF: A primary mediator of the host response. Anna. Rev. Immunol. 7, 625–655 (1989).

    CAS  Article  Google Scholar 

  3. 3

    Colombo, M.P. & Forni, G. Cytokine gene transfer in tumor inhibition and tumor therapy; where are we now? Immunol. Today 15, 48–51 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Fearon, E.R. et al. lnterleukin-2 production by tumor Cell bypasses T helper function in the generation of an antitumor response. Cell 60, 397–403 (1990).

    CAS  Article  Google Scholar 

  5. 5

    Hock, H. et al. Mechanisms of rejection induced by tumor Cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon γ. Proc. Notl. Acad. Sci. USA 90, 2774–2778 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Cavallo, F. et al. Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene transfection. J. Immunol. 149, 3627–3635 (1992).

    CAS  PubMed  Google Scholar 

  7. 7

    Maass, G. et al. Priming of tumor-specific T Cells in the draining lymph nodes after immunization with interleukin 2-secreting tumor Cells: Three consecutive stages may be required for successful tumor vaccination. Proc. Natl. Acad. Sci. USA 92, 5540–5544 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Tepper, R.I., Pattengale, P.K. & Leder, P. Murine interleukin-4 displays potent antitumor activity in vivo. Cell 57, 503–512 (1989).

    CAS  Article  Google Scholar 

  9. 9

    Tepper, R.I., Coffman, R.L. & Leder, P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science 257, 548–551 (1992).

    CAS  Article  Google Scholar 

  10. 10

    Golumbek, P.T. et al. Treatment of established renal cancer by tumor Cells engineered to secrete interleukin-4. Science 254, 713–716 (1991).

    CAS  Article  Google Scholar 

  11. 11

    Hock, H., Dorsch, M., Diamantstein, T. & Blankenstein, T.J. Interleukin 7 induces CD4+ T Cell-dependent tumor rejection. J. Exp. Med. 174, 1291–1298 (1991).

    CAS  Article  Google Scholar 

  12. 12

    Watanabe, Y. et al. Exogeneous expression of mouse interferon-gamma cDNA in mouse neuroblastoma C1300 Cells results in reduced tumorigenicity by augmented antitumor immunity. Proc. Natl. Acad. Sci. USA. 86, 9456–9460 (1989).

    CAS  Article  Google Scholar 

  13. 13

    Blankenstein, T. et al. Tumor suppression after tumor Cell-targeted tumor necrosis factor α gene transfer. J. Exp. Med. 173, 1047–1052 (1991).

    CAS  Article  Google Scholar 

  14. 14

    Asher, A.L. et al. Murine tumor Cells transduced with the gene for tumor necrosis factor-α: Evidence for paracrine effects of tumor necrosis factor against tumors. J. Immunol. 146, 3227–3234 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Suda, T., Takahashi, T., Golstein, P. & Nagata, S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75, 1169–1178 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Suda, T. et al. Expression of the Fas ligand in Cells of T Cell lineage. J. Immunol. 154, 3806–3813 (1995).

    CAS  Google Scholar 

  17. 17

    Arase, H., Arase, N. & Saito, T. Fas-mediated cytotoxicity by freshly isolated natural killer Cells. J. Exp. Med. 181, 1235–1238 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Kayagaki, N. et al. Metalloproteinase-mediated release of human Fas ligand. J. Exp. Med. 182, 1777–1783 (1995).

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 20

    Yonehara, S., Ishii, A. & Yonehara, M. A Cell-killing monoclonal antibody (anti-Fas) to a Cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J. Exp. Med. 169, 1747–1756 (1989).

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Rensing-Ehl, A. et al. Local Fas/APO-1 (CD95) ligand-mediated tumor Cell killing in vivo. Eur. J. Immunol. 25, 2253–2258 (1995).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

    Abreu-Martin, M.T., Vidrich, A., Lynch, D.H. & Targan, S.R. Divergent induction of apoptosis and IL-8 secretion in HT-29 Cells in response to TNF-α and ligation of Fas antigen. J. Immunol. 155, 4147–4154 (1995).

    CAS  Google Scholar 

  25. 25

    Tanaka, M., Suda, T., Takahashi, T. & Nagata, S. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J. 14, 1129–1135 (1995).

    CAS  Article  Google Scholar 

  26. 26

    Iwai, K. et al. Differential expression of bcl-2 and susceptibility to anti-Fas-mediated Cell death in peripheral blood lymphocytes, monocytes, and neutrophils. Blood 84, 1201–1208 (1994).

    CAS  Google Scholar 

  27. 27

    Liles, W.C., Kiener, P.A., Ledbetter, J.A., Aruffo, A. & Klebanoff, S.J. Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: Implications for the regulation of apoptosis in neutrophils. J. Exp. Med. 184, 429–440 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Luger, T.A. & Schwartz, T. Evidence for an epidermal cytokine network. J. Invest. Dermatol. 90, 100s–104s (1990).

    Article  Google Scholar 

  29. 29

    Mckenzie, R.C. & Sauder, D.N. The role of keratinocyte cytokines in inflammation and immunity. J. Invest. Dermatol. 90, 105s–107s (1990).

    Article  Google Scholar 

  30. 30

    Lichtenstein, A. & Kahle, J. Antitumor effect of inflammatory neutrophils; characteristics of in vivo generation and in vitro tumor Cell lysis. Int. J. Cancer 35, 121–127 (1985).

    CAS  Article  Google Scholar 

  31. 31

    Bellgrau, D. et al. A role for CD95 ligand in preventing graft rejection. Nature 377, 630–632 (1995).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    Wilbanks, G.A., Mammolenti, M. & Streilein, J.W. Studies on the induction of anterior chamber-associated immune deviation (ACAID) III. Induction of ACAID depends upon intraocular transforming growth factor-β. Eur. J. Immunol. 22, 165–173 (1992).

    CAS  Article  Google Scholar 

  34. 34

    Gresham, H.D., Ray, C.J. & O'Sullivan, F.X. Defective neutrophil function in the autoimmune mouse strain MRL/lpr. Potential role of transforming growth factor-beta J. Immunol. 146, 3911–3921 (1991).

    CAS  PubMed  Google Scholar 

  35. 35

    Lowrance, J.H., O'Sullivan, F.X., Caver, T.E., Waegell, W. & Gresham, H.D. Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice. J. Exp. Med. 180, 1693–703 (1994).

    CAS  Article  Google Scholar 

  36. 36

    Braun, M.Y., Lowin, B., French, L., Acha-Orbea, H. & Tschopp, J. Cytotoxic T Cells deficient in both functional Fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J. Exp. Med. 183, 657–661 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Baker, M.B., Altman, N.H., Podack, E.R. & Levy, R.B. The role of Cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J. Exp. Med. 183, 2645–2656 (1996).

    CAS  Article  Google Scholar 

  38. 38

    Saito, K., Yagita, H., Okumura, K. & Azuma, M. Eur. J. Immunol 26, 3098–3106 (1996).

    CAS  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

  40. 40

    Ando, K. et al. Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J. Exp. Med. 178, 1541–1554 (1993).

    CAS  Article  Google Scholar 

  41. 41

    Seung, L.P., Rowley, D.A., Dubey, P. & Schreiber, H. Synergy between T-Cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc. Natl. Acad. Sci. USA 92, 6254–6258 (1995).

    CAS  Article  Google Scholar 

  42. 42

    Townsend, S.E. & Allison, J.P. Tumor rejection after direct costimulation of CD8+ Cells by B7-transfected melanoma Cells. Science 259, 368–370 (1993).

    CAS  Article  Google Scholar 

  43. 43

    Kojima, H. et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity 1, 357–364 (1994).

    CAS  Article  Google Scholar 

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Affiliations

  1. Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113, Japan

    Ken-Ichiro Seino, Nobuhiko Kayagaki, Ko Okumura & Hideo Yagita

  2. Department of Surgery, University ofTsukuba School of Medicine, Tsukuba Science City, Ibaraki, 305, Japan

    Ken-Ichiro Seino

  3. CREST, Japan Science and Technology Corporation (JST), Chiyoda-ku, Tokyo, 101, Japan

    Ko Okumura & Hideo Yagita

Authors
  1. Ken-Ichiro Seino
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  2. Nobuhiko Kayagaki
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  3. Ko Okumura
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  4. Hideo Yagita
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Seino, KI., Kayagaki, N., Okumura, K. et al. Antitumor effect of locally produced CD95 ligand. Nat Med 3, 165–170 (1997). https://doi.org/10.1038/nm0297-165

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