Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

Abstract

Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis.

KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity

“…2C, 2F). Variability in cytokine production between donors was evident, as previously reported (43); however, KIR2DS2 high NK cells were significantly associated with increased cytokine production (Fig. 2).…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…Monalizumab (IPH2201), a humanized monoclonal anti-NKG2A blocking antibody, has also shown promising preclinical results against hematologic and solid tumors ( 185 , 186 ), which have prompted to evaluate its efficacy in clinical trials either as monotherapy or combined with other treatments ( 187 ). Other strategies to inhibit the NKG2A/HLA-E axis are based on NKG2A downregulation in NK cells by dasatinib ( 188 ), or the reduction of HLA-E levels in tumor cells, by drugs such as bortezomib, dinaciclib or selinexor, tested in vitro on MM, AML, and lymphoma, respectively ( 189 – 191 ). Mechanistically, dasatinib treatment inhibits p38 mitogen-activated protein kinase (MAPK), diminishing the import of NKG2A transcription factor GATA-3 to the cell nuclei ( 188 ).…”

“…Constant de novo protein synthesis is essential for maintaining HLA-E surface expression levels. Consequently, selinexor induced degradation of nuclear export protein exportin-1 (XPO1), which regulates the transport of ribosomal subunits from nucleus to cytoplasm, decreases the number of HLA-E molecules in plasma membrane, mainly because of the reduction of HLA-E binding substrates ( 191 ). Although the action mechanism of dinaciclib has not yet been elucidated, the administration of this cyclin-dependent kinase (CDK) inhibitor prior to NK cell infusion further boosts their killing activity in an AML mouse model ( 190 ).…”

Therapeutics to harness the immune microenvironment in multiple myeloma

“…Selinexor has been FDA-approved for use combined with dexamethasone and bortezomib in MM patients previously treated with four prior therapies, including at least two PIs and at least two IMiDs [82,83] . XPO1 overexpression is linked with a worse prognosis in solid tumors and blood cancers [84] . Selinexor also demonstrates an ability to modulate tumor immunology and the surrounding tumor microenvironment.…”

“…Selinexor also demonstrates an ability to modulate tumor immunology and the surrounding tumor microenvironment. Treatment of B cell lymphomas with selinexor led to increased NK cell-mediated cytotoxicity in vitro and selinexor potentiated ADCC-mediated by rituximab and obinutuzumab [ 85 ] . NK cells exhibited greater IFN-γ and CD107a expression, both activities associated with NK activation, and lymphoma cells downregulated HLA-E, which binds the inhibitory NKG2A receptor.…”