Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression

ROSSI, LUCAS EZEQUIEL; ÁVILA, DAMIÁN EZEQUIEL; SPALLANZANI, RAÚL GERMÁN; ZIBLAT, ANDREA; FUERTES, MERCEDES BEATRIZ; LAPYCKYJ, LARA; CROCI, DIEGO; RABINOVICH, GABRIEL ADRIÁN; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER

JOURNAL OF LEUKOCYTE BIOLOGY

FEDERATION AMER SOC EXP BIOL

Año: 2011 vol. 91 p. 321 - 331

0741-5400

Histone deacetylase inhibitors (HDACi) are being used as 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 Trichostatin A (TSA), sodium valproate (VPA) and sodium butyrate (NaB) inhibited IFN-g production by CD56dim and CD56bright 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-g secretion upon re-stimulation of NK cells with IL-2, while 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-g 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.