Ewing Sarcoma Cells Are Sensitized to NK Cell Mediated Killing by SNDX-275, An HDAC Inhibitor

Abstract 1126

Natural Killer (NK) cells are an important a part of the innate immune system response to infection and malignancy. Tumors may escape NK cell surveillance by upregulating expression of inhibitory ligands (HLA), or downregulating expression of activating ligands (MICA/B, ULBP). Histone Deacetylase (HDAC) inhibitors promote cell cycle arrest, differentiation, and apoptosis in tumor cells by decompacting chromatin to a more transcriptionally active state. In previous studies, we and others have shown that HDACi can sensitize tumor cells to NK cell mediated cytotoxicity by modulating expression of activating or inhibitory receptors. We investigated whether HDACi could modulate sensitivity of Ewing Sarcoma (EWS) cell lines to lysis by NK cells. EWS cells were cultured in vitro in the presence of SNDX-275, a Class I HDAC inhibitor, for 24, 48 and 72 hours, and then assessed for viability, cell proliferation, expression of activating and inhibitory receptors, and susceptibility to NK cell mediated cytolysis. We found a dose and time dependent inhibition of EWS cell proliferation mediated by SNDX-275. We also found a dose and time dependent decrease in the expression of HLA on tumor cell surface, which correlated with drug treated cells being more susceptible to NK cell mediated killing. SNDX-275 not only has a direct toxicity on Ewing sarcoma cells but it also appears to improve NK cell mediated cytolysis of these cells by down regulation of HLA, an inhibitory receptor of NK cells.