The Journal of Experimental Medicine
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Published 15 November 2004. doi:10.1084/jem.20041522
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 10, 1325-1335
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NKG2D Recognition and Perforin Effector Function Mediate Effective Cytokine Immunotherapy of Cancer

Mark J. Smyth1, Jeremy Swann1, Janice M. Kelly1, Erika Cretney1, Wayne M. Yokoyama2, Andreas Diefenbach3, Thomas J. Sayers4, and Yoshihiro Hayakawa1

1 Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, 8006 Victoria, Australia
2 Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110
3 Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016
4 Basic Research Program, SAIC-Frederick Inc., National Cancer Institute, Frederick, MD 21702

Address correspondence to Mark Smyth, Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St., 8006, Victoria, Australia. Phone: 61-3-9656-3728; Fax: 61-3-9656-1411; email: mark.smyth{at}petermac.org

Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D–NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor–related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.

Key Words: tumor • NK cell • Fas ligand • IL-2 • IL-18

Abbreviations used in this paper: asGM1, asialo GM1; FasL, Fas ligand; pfp, perforin; MIC, MHC class I chain–related molecule; TRAIL, TNF-related apoptosis-inducing ligand.


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