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

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 immu...

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Autores principales:	Jack G. Fisher, Christopher J. Walker, Amber DP. Doyle, Peter WM. Johnson, Francesco Forconi, Mark S. Cragg, Yosef Landesman, Salim. I. Khakoo, Matthew D. Blunt
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	NK cells natural killer cells selinexor NKG2A HLA-E XPO1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3bc2ec99a6694182a242490b99350987
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spelling	oai:doaj.org-article:3bc2ec99a6694182a242490b993509872021-12-02T00:37:08ZSelinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E2234-943X10.3389/fonc.2021.785635https://doaj.org/article/3bc2ec99a6694182a242490b993509872021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.785635/fullhttps://doaj.org/toc/2234-943XSelinexor 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.Jack G. FisherChristopher J. WalkerAmber DP. DoylePeter WM. JohnsonFrancesco ForconiMark S. CraggYosef LandesmanSalim. I. KhakooMatthew D. BluntFrontiers Media S.A.articleNK cellsnatural killer cellsselinexorNKG2AHLA-EXPO1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NK cells natural killer cells selinexor NKG2A HLA-E XPO1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	NK cells natural killer cells selinexor NKG2A HLA-E XPO1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jack G. Fisher Christopher J. Walker Amber DP. Doyle Peter WM. Johnson Francesco Forconi Mark S. Cragg Yosef Landesman Salim. I. Khakoo Matthew D. Blunt Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
description	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.
format	article
author	Jack G. Fisher Christopher J. Walker Amber DP. Doyle Peter WM. Johnson Francesco Forconi Mark S. Cragg Yosef Landesman Salim. I. Khakoo Matthew D. Blunt
author_facet	Jack G. Fisher Christopher J. Walker Amber DP. Doyle Peter WM. Johnson Francesco Forconi Mark S. Cragg Yosef Landesman Salim. I. Khakoo Matthew D. Blunt
author_sort	Jack G. Fisher
title	Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
title_short	Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
title_full	Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
title_fullStr	Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
title_full_unstemmed	Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E
title_sort	selinexor enhances nk cell activation against malignant b cells via downregulation of hla-e
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3bc2ec99a6694182a242490b99350987
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Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E

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