Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects
J. Clin. Invest. Christophe Borg, et al. 114:379 doi:10.1172/JCI21102 [Go to this article.]

Figure 4
Gleevec endowed DCs with NK cell stimulatory capacity. (A) Mouse DCs pretreated with Gleevec exhibited enhanced NK cell stimulatory capacity in vitro. BM-DC+NK coculture supernatants were monitored for IFN-γ secretion. Gleevec alone or FL+Gleevec did not trigger NK cell cytotoxicity or IFN-γ production in the absence of BM-DCs. (B) Gleevec but not tyrphostin (AG957) enhanced the NK stimulatory activity of DCs. Experiments were conducted in triplicate at various DC/NK ratios (1:2, 1:10) in the presence of Gleevec or tyrphostin. (C) IL-12 is not involved in the Gleevec-mediated NK cell activation. Conventions as in A but using IL-12p35 loss-of-function BM-DCs instead of WT BM-DCs. (D) STI-mediated NK cell activation depends on cell-cell contact. BM-DC and NK cell cocultures were separated or not by a trans-well membrane (BM-DC // NK). (E) Long-term exposure to Gleevec enhanced the host CD11c⁺ DC capacity to activate NK cells. Cell-sorted CD11c⁺ B220^– splenocytes from C57BL/6 mice treated either with H₂O or Gleevec for 15–21 days were incubated for 20 hours with NK cells as in A. IFN-γ release was measured. One representative experiment (out of 2) is shown. (F) Human CD34⁺-derived DCs stimulated with Gleevec also promoted NK cell activation. After coculture of CD34⁺-derived DCs with purified human NK cells, NK cell cytolytic activity was observed against K562. Means of triplicate wells are represented (standard errors were consistently less than 10% of means). One representative experiment (out of 5) is depicted. Groups were compared by ANOVA using the nonparametric Kruskall-Wallis test (*P < 0.05).