Research Publications

Back

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


Smyth, MJ; Wallace, ME; Nutt, SL; Yagita, H; Godfrey, DI; Hayakawa, Y
2005-06-20
JOURNAL OF EXPERIMENTAL MEDICINE
Journal Article
201
12
1973-1985
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 perform-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.
ROCKEFELLER UNIV PRESS
NATURAL-KILLER-CELLS; ALPHA-GALACTOSYLCERAMIDE KRN7000; MEDIATED TUMOR REJECTION; IN-VIVO; DENDRITIC CELLS; CUTTING EDGE; IFN-GAMMA; INTERFERON-GAMMA; HEPATIC METASTASIS; ANTITUMOR IMMUNITY
10.1084/jem.20042280
Refer to copyright notice on published article.

Back
Creation Date 2005-06-20 12:00:00