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.
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DOI：
10.1038/s41375-023-01984-z
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发表时间：
2023-10
期刊：
影响因子：
11.4
通讯作者：
Blunt, Matthew D.
中科院分区：
文献类型：
--
作者：
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.;Blunt, Matthew D.
目前正在临床研究中的第一种exportin-1（XPO 1）抑制剂selinexor与BTK抑制剂ibetinib联合治疗慢性淋巴细胞白血病（CLL）或非霍奇金淋巴瘤患者。Selinexor通过肿瘤抑制蛋白的核保留诱导肿瘤细胞的凋亡，并且最近还被描述为调节针对淋巴瘤细胞的自然杀伤（NK）细胞和T细胞的细胞毒性。在这里，我们证明XPO 1抑制通过下调HLA-E和上调TRAIL死亡受体DR 4和DR 5来增强NK细胞对原代CLL细胞的效应功能。此外，selinexor与几种批准的治疗组合增强NK细胞对CLL细胞的活化; acalabrutinib，利妥昔单抗和obinutuzumab。我们进一步证明了淋巴结相关信号（IL-4 + CD 40 L）通过上调HLA-E抑制NK细胞对CLL细胞的活化，并且抑制XPO 1可以克服这种保护作用。这些发现允许设计更有效的组合策略来利用NK细胞效应子功能对抗CLL。
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.
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