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Updated: Jul 20, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression
Jack G Fisher1, Amber D P Doyle1, Lara V Graham1
1School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
Abstract:
The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.
Insights
Exportin-1 (XPO1) inhibition by selinexor enhances natural killer (NK) cell activity against chronic lymphocytic leukemia (CLL) cells. This approach overcomes protective signals and improves NK cell-mediated anti-cancer immunity.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Selinexor, a first-in-class exportin-1 (XPO1) inhibitor, is being investigated for hematologic malignancies.
- XPO1 inhibition affects tumor suppressor protein nuclear retention and immune cell cytotoxicity.
- Natural killer (NK) cells play a crucial role in anti-lymphoma immunity.
Purpose of the Study:
- To investigate the effect of XPO1 inhibition on NK cell effector function against chronic lymphocytic leukemia (CLL) cells.
- To explore combination strategies involving XPO1 inhibition and other CLL treatments.
- To understand how lymph node-associated signals impact NK cell activation in CLL.
Main Methods:
- Treatment of primary CLL cells with selinexor.
- Assessment of NK cell cytotoxicity and effector function.
- Analysis of HLA-E and TRAIL death receptor expression.
- Evaluation of selinexor in combination with acalabrutinib, rituximab, and obinutuzumab.
- Investigation of lymph node-associated signals (IL-4 + CD40L) and XPO1 inhibition.
Main Results:
- XPO1 inhibition downregulates HLA-E and upregulates TRAIL death receptors (DR4, DR5) on CLL cells, enhancing NK cell effector function.
- Selinexor potentiates NK cell activation against CLL cells when combined with acalabrutinib, rituximab, and obinutuzumab.
- Lymph node-associated signals (IL-4 + CD40L) inhibit NK cell activation via HLA-E upregulation, an effect overcome by XPO1 inhibition.
Conclusions:
- XPO1 inhibition enhances NK cell-mediated immunity against CLL by modulating key surface receptors.
- Selinexor demonstrates potential as a combination therapy to improve NK cell anti-leukemia activity.
- Targeting XPO1 offers a promising strategy to overcome immune suppression in the CLL microenvironment.
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