IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos

Abstract

<jats:title>Abstract</jats:title> <jats:p>Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.</jats:p>

CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents

“…On the other hand, lenalidomide potentiated DARA-induced ADCC against MM cells by directly stimulating NK cells without modifying CD38 expression on these cells. Overall these evidences indicate that the clinical synergistic effect of the combination of lenalidomide and DARA is likely due either to the increased CD38 expression on MM cells or to the stimulation of NK activity [52].…”

“…In particular, CD38 was up regulated after IMiDs treatment whereas ITGA8 and ICAM2 (CD102) were both down-regulated [51]. More recently, Fedele P. et al [52] reported that lenalidomide treatment increases CD38 expression in several human myeloma cell lines, through Ikaros and Aiolos degradation. Thereafter, the authors tested the hypothesis that the additive effect observed by the combination of anti-CD38 mAbs and IMiDs in vitro could be due to the upregulation of CD38 by IMiDs [52].…”

“…More recently, Fedele P. et al [52] reported that lenalidomide treatment increases CD38 expression in several human myeloma cell lines, through Ikaros and Aiolos degradation. Thereafter, the authors tested the hypothesis that the additive effect observed by the combination of anti-CD38 mAbs and IMiDs in vitro could be due to the upregulation of CD38 by IMiDs [52]. They found that the additive effect of the treatment combination was directly correlated with the increased CD38 surface expression on MM cells [52].…”

“…Thereafter, the authors tested the hypothesis that the additive effect observed by the combination of anti-CD38 mAbs and IMiDs in vitro could be due to the upregulation of CD38 by IMiDs [52]. They found that the additive effect of the treatment combination was directly correlated with the increased CD38 surface expression on MM cells [52]. However, in the presence of lenalidomide it was not observed any additional effect on DARA direct cytotoxicity [52].…”

“…They found that the additive effect of the treatment combination was directly correlated with the increased CD38 surface expression on MM cells [52]. However, in the presence of lenalidomide it was not observed any additional effect on DARA direct cytotoxicity [52]. On the other hand, lenalidomide potentiated DARA-induced ADCC against MM cells by directly stimulating NK cells without modifying CD38 expression on these cells.…”