The Journal of Experimental Medicine
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Published 20 June 2005. doi:10.1084/jem.20042280
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 12, 1973-1985
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ARTICLE

 Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer

Mark J. Smyth1, Morgan E. Wallace1, Stephen L. Nutt2, Hideo Yagita3, Dale I. Godfrey4, and Yoshihiro Hayakawa1

1 Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia
2 The Walter and Eliza Hall Institute for Medical Research, Parkville Victoria, 3050, Australia
3 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
4 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

CORRESPONDENCE Mark J. Smyth: mark.smyth{at}petermac.org

The CD1d reactive glycolipid, {alpha}-galactosylceramide ({alpha}-GalCer), potently activates T cell receptor-{alpha} type I invariant NKT cells that secondarily stimulate the proliferation and activation of other leukocytes, including NK cells. Here we report a rational approach to improving the antitumor activity of {alpha}-GalCer by using delayed interleukin (IL)-21 treatment to mature the {alpha}-GalCer–expanded pool of NK cells into highly cytotoxic effector cells. In a series of experimental and spontaneous metastases models in mice, we demonstrate far superior antitumor activity of the {alpha}-GalCer/IL-21 combination above either agent alone. Superior antitumor activity was critically dependent upon the increased perforin-mediated cytolytic activity of NK cells. Transfer of {alpha}-GalCer–pulsed dendritic cells (DCs) followed by systemic IL-21 caused an even more significant reduction in established (day 8) metastatic burden and prolonged survival. In addition, this combination prevented chemical carcinogenesis more effectively. Combinations of IL-21 with other NK cell–activating cytokines, such as IL-2 and IL-12, were much less effective in the same experimental metastases models, and these cytokines did not substitute effectively for IL-21 in combination with {alpha}-GalCer. Overall, the data suggest that NK cell antitumor function can be enhanced greatly by strategies that are designed to expand and differentiate NK cells via DC activation of NKT cells.

Abbreviations used: {alpha}-GalCer, {alpha}-galactosylceramide; FasL, Fas ligand; Flt3L, fms-like tyrosine kinase 3 ligand; iNKT, invariant type I NKT; MCA, methylcholanthrene; pfp, perforin; pIL-21, plasmid IL-21; pORF, plasmid open reading frame; TRAIL, TNF-related apoptosis-inducing ligand.


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