School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
School of Cancer Sciences, University of Southampton, Southampton, UK.
Leukemia. 2023 Oct;37(10):2036-2049. doi: 10.1038/s41375-023-01984-z. Epub 2023 Aug 1.
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.
目前，一种新型的核输出蛋白 1（XPO1）抑制剂 selinexor 正在与 BTK 抑制剂伊布替尼联合用于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内滞留诱导肿瘤细胞凋亡，最近也被描述为调节自然杀伤（NK）细胞和 T 细胞对淋巴瘤细胞的细胞毒性。在这里，我们证明 XPO1 抑制通过下调 HLA-E 和上调 TRAIL 死亡受体 DR4 和 DR5 来增强 NK 细胞对原发性 CLL 细胞的效应功能。此外，Selinexor 与几种已批准的治疗方法（阿卡替尼、利妥昔单抗和奥滨尤妥珠单抗）联合增强了对 CLL 细胞的 NK 细胞激活作用。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 NK 细胞对 CLL 细胞的激活，而 XPO1 的抑制可以克服这种保护作用。这些发现为设计更有效的联合策略以利用 NK 细胞对 CLL 的效应功能提供了依据。
