XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.
Humans
Karyopherins
/ antagonists & inhibitors
Killer Cells, Natural
/ metabolism
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Receptors, Cytoplasmic and Nuclear
/ antagonists & inhibitors
Hydrazines
/ pharmacology
Histocompatibility Antigens Class I
/ metabolism
Exportin 1 Protein
HLA-E Antigens
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
09
03
2023
accepted:
21
07
2023
revised:
03
07
2023
medline:
4
10
2023
pubmed:
2
8
2023
entrez:
1
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37528310
doi: 10.1038/s41375-023-01984-z
pii: 10.1038/s41375-023-01984-z
pmc: PMC10539165
doi:
Substances chimiques
Karyopherins
0
selinexor
31TZ62FO8F
Receptors, Cytoplasmic and Nuclear
0
Hydrazines
0
Histocompatibility Antigens Class I
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2036-2049Subventions
Organisme : Medical Research Council
ID : MR/S009388/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N014308/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/MO19829/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C42023/A29370
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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