It is assumed that tumor cells are poorly immunogenic and not recognized by the immune system because proinflammatory signals required for DC activation are missing in vivo. However, NK cell activation, either spontaneously induced by the characteristics of the tumor cell transplanted (e.g., MHC class I low, TAP deficient) [80-82] or forced by overexpression on the tumor cells of NKG2D ligands [83,84], CD27 , or gp96 , has been shown to promote the elicitation of cognate and protective immune responses to the tumor [57, 58,85,86]. IFN-y secreted during NK cell-mediated tumor rejection is critical for CTL generation, particularly when tumors express CD70 or CD80 and CD86. However, tumor rejection following recognition of NKG2D ligands by NK cells led to CTL development in the absence of IFN-y but required CD4+ T cell help .
Following the studies of Fernandez etal.  demonstrating the relevance of DC-mediated NK cell activation in tumor rejection in a model of MHC class I low mesothelioma, we  showed that modulation of the c-kit tyrosine kinase signaling pathway in DC by imatinib mesylate (STI571/Gleevec) led to marked NK cell activation in various strains of mice. Indeed, 10- to 21-day oral therapy with STI571 promoted the selective expansion of CD69+ NK cells and NK cell-dependent antitumor effects in tumor transplantation models using cells that were resistant to STI571 in vitro. This antitumor effect was augmented by pretreatment of mice with the DC growth factor Flt3-L. In vitro studies in which BM-DC propagated in the presence of GM-CSF and IL-4 were incubated in the presence of increasing doses of STI571 highlighted that nanomolar concentrations of STI571 were sufficient to endow DC with the ability to stimulate NK cells in vitro but did not promote DC maturation (Fig. 1c). The activation of NK cell IFNy secretion by STI571-stimulated DC was not dependent on IL-12 but required cell-to-cell contacts. STI571 likely acted by inhibiting the c-kit pathway in DC because identical results were obtained by utilizing the pharmacological agent or DC from c-kit loss-of-function mutant W/Wv mice. The ability of STI571 to endow DC with NK cell stimulatory capacities was also achieved in a human setting using CD34+ progenitors propagated in GM-CSF and TNF. Importantly, we could show that up to 50% of patients bearing a gastrointestinal sarcoma (GIST) and treated with STI571 acquired enhanced NK cell effector functions. Specifically, the levels of NK cell IFN-y secretion promoted by ex vivo stimulation with mature DC were significantly enhanced 3- to 50-fold in patients treated for 2 months with STI571. The relevance of NK cell activation was suggested by a significant positive correlation between early NK cell trigger ing at 2 months and the objective clinical response at 1 year in a cohort of 42 patients, and importantly, the time to progression is significantly longer in patients exhibiting NK cell activation during the first 2 months of therapy. GIST cells display many of the typical features of NK cell sensitivity (TAP1 deficiency, overexpression of MIC and ULBP at mRNA and protein levels, loss of MHC class I molecules) and are lysed by NK cells derived from normal volunteers as efficiently as the prototypic highly NK susceptible K562 cells . NK cells from 50% of GIST patients at diagnosis displayed downregulation of NKG2D expression that was not restored by STI571 despite clinical responses. The study of circulating DC in these patients may highlight some interesting findings pertaining to the DC/NK cell dialogue in vivo.
With groundbreaking data from clinical trials, Ruggeri et al. highlighted that mismatch of NK cell receptors and ligands during haploidentical bone marrow transplantation may be used to enhance engraftment and to prevent leukemia relapse by boosting graft-versus-leukemia effects without augmenting the risk of developing graft-versus-host disease . However, HLA-C/KIR mismatches between residual recipient leukemic cells and donor NK cells might not fully account for NK cell activation in vivo, and host DC might play a critical role for NK cell triggering in this setting [88, 89]. Indeed, the cytokine storm associated with graft conditioning and/or concomitant infectious agents could promote DC maturation and NK cell activation. Nevertheless, the success of donor lymphocyte infusion in controlling residual disease in chronic myeloid leukemia (CML) patients with the BCR/ABL translocation remains poorly understood. We hypothesized  that the BCR/ABL translocation in myeloid DC might confer to DC selective NK cell stimulatory capacities in the absence of danger signals. We  have shown that monocyte-derived DC from CML patients were selectively endowed with NK cell stimulatory capacity. Using a gene transfer approach in mouse bone marrow progenitors, we demonstrated that BCR/ABL promoted DC-mediated NK cell activation. The DC-NK cell cross-talk promoted by the BCR/ABL translocation appears unique because JunB or interferon consensus sequence binding protein (ICSBP) loss of functions, which are also associated with other myeloproliferative disorders, did not promote DC-mediated NK cell activation. NK cell activation by BCR/ABL-expressing DC involved enhancement of expression of NKG2D activating receptors, and both NK cell activation and NKG2D enhancement were blocked by STI571 (Fig. 1d). Moreover, although NK cells from CML-developing mice did not secret IFNy in response to IL-2, they responded to autologous BCR/ABL DC. We confirmed in CML patients that CML DC overexpressed NKG2D lig-ands and that CML DC-induced NK cell killing activity is partially inhibited by either STI571 or anti-NKG2D neutralizing antibody (Fig. 1d). However, CML DC were not mature and displayed only poor allostimulatory activities .
Therefore, the clonal BCR/ABL DC displayed the unique and selective ability to activate NK cells, suggesting that they may participate in the NK cell control of CML. Thus the treatment of CML patients with STI571, although critical at the early stage for its direct antileukemic effects reducing the tumor burden, might have at later stages a deleterious effect on the host DC-NK cell interaction.
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