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
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Irene Veneziani1, Doriana Fruci2, Mirco Compagnone2, Vito Pistoia1, Paolo Rossi3,4 and Loredana Cifaldi3
1Department of Immunology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
2Department of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
3Academic Department of Pediatrics (DPUO), Bambino Gesù Children’s Hospital, Rome, Italy
4Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
Loredana Cifaldi, email: [email protected]
Keywords: neuroblastoma; MYCN oncogene; BET-bromodomain inhibitor JQ1; ligands for NK cell-activating receptors; tumor immune escape
Received: June 21, 2018 Accepted: February 15, 2019 Published: March 15, 2019
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 ligands for NK cell-activating receptors. These results suggest that the use of JQ1 should be discourage in combination with NK cell-based immunotherapy in a perspective chemotherapeutic treatment of NB. Thus, further investigations, exploiting molecular strategies aimed to boost the NK cell-mediated killing of NB cells, are warranted.
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