Selinexor potentiates NK cell activation against multiple myeloma.

INTRODUCTION: Selinexor is a first in class selective inhibitor of nuclear export (SINE) targeting Exportin-1 (XPO1) and approved for the treatment of multiple myeloma (MM). Selinexor has previously been shown to enhance natural killer (NK) cell activation against lymphoma cells via disruption of the NKG2A: HLA-E immune checkpoint axis. METHODS: MM cell lines (L363, U266, MM.1S) and primary myeloma cells isolated from the bone marrow of patients were exposed to selinexor (50-2000 nM) with or without IFNγ or IL-6 to mimic the tumour microenvironment (TME). Surface HLA-E and total HLA class I were quantified by flow cytometry. Immunoblotting and a range of functional assays were used to examine the effect of selinexor on NK cell effector function against MM. RESULTS: Selinexor downregulated surface HLA-E expression on MM cell lines and primary myeloma cells. This improved the activation of NKG2A+ NK cells, NK cell-specific lysis of MM cell lines and antibody-dependent cellular cytotoxicity (ADCC) with the therapeutic antibodies daratumumab and elotuzumab. This improvement was also observed in the presence of TME-mimicking signals IFNγ and IL-6. Pre-treatment of MM cells with selinexor for 24 hours prior to daratumumab resulted in optimal ADCC. DISCUSSION: These data reveal that selinexor selectively disrupts the NKG2A:HLA-E immune checkpoint axis in MM and enhances NK cell activation and ADCC against MM cells. These findings provide a mechanistic rationale for investigating combinations of selinexor with approved therapeutic antibodies in MM and suggest that treatment timing may be an important consideration in the design of combination regimens.