Histone deacetylase inhibitors compromise NK cell viability and effector functions through downregulation of activating receptor expression

ROSSI, LUCAS EZEQUIEL; ÁVILA, DAMIÁN EZEQUIEL; SPALLANZANI, RAÚL GERMÁN; ZIBLAT, ANDREA; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER

Buenos Aires, Argentina

Congreso; 1º Congreso Franco-Argentino de Inmunología; 2010

Sociedad Argentina de Inmunología y French Society of Immunology

Inhibition of histone deacetylases (HDAC) with HDAC inhibitors (HDACi) is a promisingapproach for the treatment of cancer patients because epigenetic anomalies are involved in thecarcinogenesis process. HDACi increase susceptibility of tumor cells to NK cell effectorfunctions in vitro, but in vivo they can also affect cells involved in immune surveillance such asNK cells. Thus, here we investigated their functional response upon exposure to HDACi.Treatment of human NK cells with Trichostatin A (TSA), a broad spectrum HDACi, reduced thepercentage IFN-g+, IFN-g+CD107a+ and CD107a+ cells from 8.8±2.7%, 9.5±4.8% and 2.5±1.0% to 0.2±0.1%, 0.2±0.1%, and 1.3±1.0%, respectively, in NK cells stimulated with IL-12+IL-15+IL- 18, and from 3.3±2.0%, 3.7±3.0% and 12.0±5.1% to 1.6±0.9%, 0.6±0.4%, and 6.2±4.3%, respectively, in NK cells co-cultured with K562 cells (p<0.05 in all cases). Inhibition of IFN-g secretion by TSA was confirmed by ELISA with cell culture supernatants. Part of the effect was due to TSA-induced NK cell apoptosis but ≈50% of the NK cells remained viable after treatment with TSA. Thus, we assessed its effects on NK cell receptor expression. Treatment with TSA for 24h significantly reduced cell surface NKG2D and NKp46 in resting NK cells in 76% and 74% respectively, and the expression of NKG2D, NKp44 and NKp46 in NK cells stimulated with IL- 12+IL-15+IL-18 in 88%, 68% and 54% respectively. Also, TSA inhibited expression of NKG2D, NKp30, NKp44 and NKp46 in 79%, 38%, 57% and 64%, respectively, in NK cells stimulated with the cytokines for 4d before the addition of the drug. Expression of these receptors was not restored when TSA was removed from the cultures. Other HDACi with a narrower specificity (sodium butyrate and sodium valproate) induced similar effects. Thus, broad spectrum HDACi compromise NK cell viability, effector function and receptor expression, suggesting that besides their anti-tumor effects, they compromise immune surveillance by NK cells.