Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E.
Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E.
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DOI：
10.3389/fonc.2021.785635
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发表时间：
2021
影响因子：
4.7
通讯作者：
Blunt MD
中科院分区：
文献类型：
--
作者：
Fisher JG;Walker CJ;Doyle AD;Johnson PW;Forconi F;Cragg MS;Landesman Y;Khakoo SI;Blunt MD
Selinexor是FDA批准的核输出蛋白exportin-1（XPO 1）的选择性抑制剂，通过肿瘤抑制蛋白的核积累引起特定的癌细胞死亡。设计赛林克斯与其他治疗药物（如免疫疗法）联合使用的合理研究，需要对赛林克斯对免疫系统的影响有基本的了解。免疫疗法的一个重要新兴领域是基于自然杀伤（NK）细胞的疗法。NK细胞功能受到来自多种激活和抑制受体的信号平衡的严格调节。因此，在癌症中，通过激活受体识别的应激配体的上调或通过抑制性受体识别的HLA I类的下调可导致抗癌NK细胞应答。因此，XPO 1功能的变化有可能通过改变这种平衡来影响NK细胞功能。因此，我们试图研究selinexor如何影响NK细胞功能。淋巴瘤细胞的Selinexor预处理显著增加了NK细胞介导的针对SU-DHL-4、JeKo-1和拉莫斯细胞的细胞毒性，同时增加了NK细胞上的CD 107 a和IFNγ表达。此外，selinexor增强了针对用抗CD 20抗体利妥昔单抗和obinutuzumab包被的淋巴瘤细胞的ADCC。在探索可能的机制，我们确定，XPO 1抑制显着降低淋巴瘤细胞系和原发性慢性淋巴细胞白血病细胞的HLA-E的表面表达。HLA-E结合抑制性受体NKG 2A，因此，赛灵克斯选择性增加NKG 2A + NK细胞的活化。我们的数据显示，除了其直接的细胞毒性活性外，赛灵克斯还通过破坏抑制性NKG 2A：HLA-E轴来激活抗癌免疫应答。
Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis.
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影响因子：
64.5
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