XPO1抑制增加慢性淋巴细胞白血病细胞对自然杀伤细胞介导的细胞毒作用的敏感性，并克服HLA-E表达。
XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.
发表日期：2023 Aug 01
作者：
Jack G Fisher, Amber D P Doyle, Lara V Graham, Shreyanshi Sonar, Ben Sale, Isla Henderson, Luis Del Rio, Peter W M Johnson, Yosef Landesman, Mark S Cragg, Francesco Forconi, Christopher J Walker, Salim I Khakoo, Matthew D Blunt
来源：
LEUKEMIA
摘要：
一类新型的exportin-1 (XPO1) 抑制剂selinexor当前正在与BTK抑制剂ibrutinib联合使用，对慢性淋巴细胞白血病(CLL)或非霍奇金淋巴瘤患者进行临床研究。Selinexor通过使肿瘤抑制蛋白核滞留来诱导肿瘤细胞凋亡，并最近被发现调节自然杀伤细胞(NK细胞)和T细胞对淋巴瘤细胞的细胞毒作用。在这里，我们证明XPO1抑制增强了NK细胞对原发性CLL细胞的效应功能，通过下调HLA-E和上调TRAIL死亡受体DR4和DR5。此外，selinexor与几种已批准的治疗方法（acalabrutinib、rituximab和obinutuzumab）联合使用能增强对CLL细胞的NK细胞激活。我们进一步证明，淋巴结相关信号(IL-4+CD40L)通过上调HLA-E抑制了NK细胞对CLL细胞的激活，而XPO1的抑制可以克服这种保护效应。这些发现为设计更有效的联合策略，利用NK细胞的效应功能对抗CLL提供了可能。© 2023. The Author(s).
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.© 2023. The Author(s).