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

Abstract

The CD1d reactive glycolipid, α-galactosylceramide (α-GalCer), potently activates T cell receptor-α 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 α-GalCer by using delayed interleukin (IL)-21 treatment to mature the α-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 α-GalCer/IL-21 combination above either agent alone. Superior antitumor activity was critically dependent upon the increased perfo..