Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer
- Author(s)
- Smyth, MJ; Wallace, ME; Nutt, SL; Yagita, H; Godfrey, DI; Hayakawa, Y;
- Details
- Publication Year 2005-06-20,Volume 201,Issue #12,Page 1973-1985
- Journal Title
- JOURNAL OF EXPERIMENTAL MEDICINE
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- ROCKEFELLER UNIV PRESS
- Keywords
- NATURAL-KILLER-CELLS; ALPHA-GALACTOSYLCERAMIDE KRN7000; MEDIATED TUMOR REJECTION; IN-VIVO; DENDRITIC CELLS; CUTTING EDGE; IFN-GAMMA; INTERFERON-GAMMA; HEPATIC METASTASIS; ANTITUMOR IMMUNITY
- Publisher's Version
- https://doi.org/10.1084/jem.20042280
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-06-20 12:00:00