The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors.

The BET-bromodomain inhibitor JQ1 renders neuroblastoma cells more resistant to NK cell-mediated recognition and killing by downregulating ligands for NKG2D and DNAM-1 receptors. Oncotarget. 2019 Mar 15;10(22):2151-2160 Authors: Veneziani I, Fruci D, Compagnone M, Pistoia V, Rossi P, Cifaldi L Abstract Low expression of ligands for NK cell-activating receptors contributes to neuroblastoma (NB) aggressiveness. Recently, we demonstrated that the expression of MYCN, a poor prognosis marker in NB, inversely correlates with that of activating ligands. This indicates that MYCN expression level can predict the susceptibility of NB cells to NK cell-mediated immunotherapy and that its downregulation can be exploited as a novel therapeutic strategy to induce the expression of activating ligands. Here we evaluated the effect of the BET-bromodomain inhibitor JQ1 on the expression of ligands for NK cell-activating receptors in NB cell lines. Although downmodulating MYCN, JQ1 impaired the expression of ligands for NK cell-activating receptors, rendering NB cell lines more resistant to NK cell-mediated killing. The downregulation of activating ligands was due to JQ1-mediated impaired functions of both c-MYC and p53, two transcription factors known to regulate the expression of ULBP1-3 ligands for NKG2D activating receptor. Moreover JQ1 strongly downregulated the levels of ROS, a stress-induced signaling event associated with the induction of ligand...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research