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XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.
- Source :
-
Leukemia [Leukemia] 2023 Oct; Vol. 37 (10), pp. 2036-2049. Date of Electronic Publication: 2023 Aug 01. - Publication Year :
- 2023
-
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.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Killer Cells, Natural metabolism
Exportin 1 Protein
HLA-E Antigens
Karyopherins antagonists & inhibitors
Karyopherins metabolism
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Receptors, Cytoplasmic and Nuclear antagonists & inhibitors
Hydrazines pharmacology
Histocompatibility Antigens Class I metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 37
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 37528310
- Full Text :
- https://doi.org/10.1038/s41375-023-01984-z