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

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 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.

Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function

“…Our bulk RNA-seq data revealed that JQ1(+) treatment led to a downregulated NK cell cytolytic response, which impacted NK cell killing of cancer cells, in part through the downregulation of NK cell activating receptors. Consistent with these findings, JQ1 has been shown to downregulate target ligands in neuroblastoma cells and downregulate NK cell activation receptors NKG2D and DNAM-1 on NK cells (40). Unlike inflammatory function, where both BRD2 and BRD4 were found to play a role in the regulation of cytokine genes, we show that when only BRD4 is perturbed do we see a significant reduction in the ability of NK cells to eliminate cancer target cells.…”

The BET family in immunity and disease

“… 115 In neuroblastoma, JQ1 impairs the expression of ULBP1–3 ligands for NKG2D activating receptor by inhibiting the transcriptional regulation of MYC and tumor protein P53 (TP53), thereby rendering NB cell lines more resistant to NK cell-mediated killing. 116 These studies demonstrate the dual role of BETs in antitumor immunity, depending on MYC status and cancer type.…”

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

“…[75]). For example, neuroblastoma tumours have a low expression of ligands (PVR, nectin-2, MICA, MICB and ULBPs) for NK cellactivating receptors DNAM-1 and NKG2D [76,77]. MYCN expression can also modulate susceptibility of neuroblastoma to NK-mediated killing: upregulation of MYCN in an inducible cell line led to downregulation of NK-activating ligands, resulting in reduced NKmediated lysis of the tumour cells [57].…”