Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer.
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.
Smyth
Mark J
MJ
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. mark.smyth@petermac.org
Wallace
Morgan E
ME
Nutt
Stephen L
SL
Yagita
Hideo
H
Godfrey
Dale I
DI
Hayakawa
Yoshihiro
Y
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000378:metabolism; D005699:Galactosylceramides / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000276:immunology / Q000628:therapy*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D000098546:Interleukin-21
D005699:Galactosylceramides; D007378:Interleukins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C493154:alpha-galactosylceramide; D054353:Perforin; D007371:Interferon-gamma; D000098546:Interleukin-21