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Original Article

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon –Dependent Natural Killer Cell Protection from Tumor Metastasis

^a Cancer Immunology, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia
^b Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702
^c Department of Pathology, The University of Sydney, Sydney, New South Wales 2006, Australia
^d Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
Cancer Immunology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St., Victoria 8006, Australia.61-3-9656-141161-3-9656-3728

m.smyth{at}pmci.unimelb.edu.au

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is expressed by in vitro activated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL-mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a subset of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)- production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, -galactosylceramide (-GalCer), a powerful inducer of NKT cell IFN- and IL-4 secretion, suppressed both liver and lung metastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL expression was not detected on NK cells from IFN-–deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and -GalCer were strictly IFN- dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN-–mediated antimetastatic effects of IL-12 and -GalCer.

Key Words: rodent • tumor immunity • in vivo animal models • immunotherapy • interleukin 12

Abbreviations used in this paper: -GalCer, -galactosylceramide; asGM1, asialo GM1; CMA, concanamycin A; MNC, mononuclear cell; pfp, perforin; TRAIL, TNF-related apoptosis-inducing ligand; WT, wild-type.

© 2001 The Rockefeller University Press

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