XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression
XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression
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.
2036-2049
Fisher, Jack G.
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Doyle, Amber D.P.
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Graham, Lara V.
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Sonar, Shreyanshi
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Sale, Ben
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Henderson, Isla
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Del Rio, Luis
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Johnson, Peter W.M.
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Landesman, Yosef
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Cragg, Mark S.
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Forconi, Francesco
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Walker, Christopher J.
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Khakoo, Salim I.
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Blunt, Matthew D.
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October 2023
Fisher, Jack G.
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Doyle, Amber D.P.
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Graham, Lara V.
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Sonar, Shreyanshi
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Sale, Ben
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Henderson, Isla
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Del Rio, Luis
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Johnson, Peter W.M.
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Landesman, Yosef
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Cragg, Mark S.
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Forconi, Francesco
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Walker, Christopher J.
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Khakoo, Salim I.
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Blunt, Matthew D.
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Fisher, Jack G., Doyle, Amber D.P., Graham, Lara V., Sonar, Shreyanshi, Sale, Ben, Henderson, Isla, Del Rio, Luis, Johnson, Peter W.M., Landesman, Yosef, Cragg, Mark S., Forconi, Francesco, Walker, Christopher J., Khakoo, Salim I. and Blunt, Matthew D.
(2023)
XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.
Leukemia, 37 (10), .
(doi:10.1038/s41375-023-01984-z).
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.
Text
s41375-023-01984-z
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More information
Accepted/In Press date: 21 July 2023
e-pub ahead of print date: 1 August 2023
Published date: October 2023
Additional Information:
Funding Information:
Research reported in this article was supported by a John Goldman Fellowship from Leukaemia UK, funding from the Medical Research Council (DTP award MR/N014308/1 and MR/MO19829/1), the Cancer Immunology Fund (University of Southampton) and Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370). We thank all of the healthy donors who donated blood used in this study and the CLL patients who donated blood in the “real-world” observational study at the University of Southampton (NIHR/UKCRN ID: 31076).
Funding Information:
Research reported in this article was supported by a John Goldman Fellowship from Leukaemia UK, funding from the Medical Research Council (DTP award MR/N014308/1 and MR/MO19829/1), the Cancer Immunology Fund (University of Southampton) and Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370). We thank all of the healthy donors who donated blood used in this study and the CLL patients who donated blood in the “real-world” observational study at the University of Southampton (NIHR/UKCRN ID: 31076).
Publisher Copyright:
© 2023, The Author(s).
Identifiers
Local EPrints ID: 480661
URI: http://eprints.soton.ac.uk/id/eprint/480661
ISSN: 0887-6924
PURE UUID: 22e37928-22b0-4bf9-b018-88cd6d9f049b
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Date deposited: 08 Aug 2023 16:39
Last modified: 18 Mar 2024 03:42
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Contributors
Author:
Jack G. Fisher
Author:
Amber D.P. Doyle
Author:
Lara V. Graham
Author:
Shreyanshi Sonar
Author:
Ben Sale
Author:
Isla Henderson
Author:
Luis Del Rio
Author:
Yosef Landesman
Author:
Christopher J. Walker
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