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Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells

Nature Medicine volume 7, pages 94–100 (2001)Cite this article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell–depleted mice or interferon-γ–deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor.

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Figure 1: Constitutive expression of TRAIL on liver NK cells.
Figure 2: Contribution of TRAIL to liver NK cell cytotoxicity; all cells prepared as effector cells.
Figure 3: Enhanced liver metastasis of L929 cells in anti-TRAIL mAb-treated CB17 SCID mice.
Figure 4: Enhanced liver metastasis of LB27.4 cells in anti-TRAIL mAb-treated CB17 SCID mice and CBF1 mice.
Figure 5: Enhanced liver metastasis of Renca cells in anti-TRAIL mAb-treated BALB/c mice.
Figure 6: Critical contribution of IFN-γ to TRAIL expresion on NK cells and TRAIL-mediated anti-metastatic effect.

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Acknowledgements

This work was supported by grant-in-aids for Scientific Research from the Princess Takamatsu Cancer Research Fund (99-23110) and the Ministry of Education, Science, and Culture, Japan. M.J.S. was supported by the National Health and Medical Research Council of Australia.We thank T. Sayers and R. Wiltrout for Renca cells and advice, and H. Akiba, H. Matsuda and E. Cretney for technical assistance.

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Authors and Affiliations

  1. Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, 113-8421, Tokyo, Japan

    Kazuyoshi Takeda, Nobuhiko Kayagaki, Noriko Yamaguchi, Hideo Yagita & Ko Okumura

  2. CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (JST), Chiyoda-ku, 101-0062, Tokyo, Japan

    Kazuyoshi Takeda, Nobuhiko Kayagaki, Noriko Yamaguchi, Hideo Yagita & Ko Okumura

  3. Department of Pathogenic Biochemistry, Research Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, 930-0194, Japan

    Yoshihiro Hayakawa

  4. Cancer Immunology, Peter MacCallum Cancer Institute, East Melbourne, 8006, Victoria, Australia

    Mark J. Smyth

  5. Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Minato-Ku, 108-8639, Tokyo, Japan

    Shigeru Kakuta & Yoichiro Iwakura

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  1. Kazuyoshi Takeda
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Correspondence to Kazuyoshi Takeda.

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Takeda, K., Hayakawa, Y., Smyth, M. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 7, 94–100 (2001). https://doi.org/10.1038/83416

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