HDACi are being used as a novel, therapeutic approach for leukemias and other hematological malignancies. However, their effect on immune cells remains ill-defined, as HDACi may impair immune surveillance. In this work, we demonstrate that TSA, VPA, and NaB inhibited IFN-γ production by CD56(dim) and CD56(bright) NK cells and NK cell-mediated cytotoxicity against K562 target cells. HDACi promoted minor NK cell apoptosis but inhibited nuclear mobilization of NF-κB p50, which was accompanied by a robust down-regulation of NKG2D and NKp46 on resting NK cells and of NKG2D, NKp44, NKp46, and CD25 on cytokine-activated NK cells. Decreased CD25 expression promoted a weakened IFN-γ secretion upon restimulation of NK cells with IL-2, whereas reduced expression of NKG2D and NKp46 was accompanied by an impaired NKG2D- and NKp46-dependent cytotoxicity. Moreover, NK cells from normal mice treated in vivo with TSA displayed a diminished expression of NK1.1, NKG2D, and NKp46 and secreted reduced amounts of IFN-γ upon ex vivo stimulation with cytokines. Thus, our preclinical results indicate that HDACi exert deleterious effects on NK cell function, which may weaken immune surveillance and facilitate relapse of the malignant disease in HDACi-treated patients.

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