Selinexor potentiates NK cell activation against multiple myeloma
Daniel T Harding, Lara V Graham, Laura G Bartlett, Nancy Gudgeon, Jack G Fisher, Christopher J Walker, Trinayan Kashyap, Charlotte E Brookes, Aidan Haslam, Graham McIlroy, Guy Pratt, Ben M Amram, Georgia Francis, Mark S Cragg, Salim I Khakoo, Sarah Dimeloe, Matthew D BluntAbstract
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.