title: Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer.
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 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.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. mark.smyth@petermac.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Wallace
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: 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
chemical_list: D005699:Galactosylceramides; D007378:Interleukins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C493154:alpha-galactosylceramide; D054353:Perforin; D007371:Interferon-gamma; D000098546:Interleukin-21