Investigation into th NK cell Immunomodulatory activity of XP01 inhibitors

核输出是通过转录因子和RNA的空间分布来调控转录和翻译的重要过程。Exportin-1(XPO1)是一种核输出蛋白，它运输关键的肿瘤抑制蛋白、癌基因mRNA和核糖体成分，在血液系统恶性肿瘤中经常被失调，以促进癌细胞的存活和增殖。Selinexor是一种XPO1的一流抑制剂，已被批准用于治疗复发和难治性多发性骨髓瘤和弥漫性大B细胞淋巴瘤。Selinexor促进肿瘤抑制蛋白在细胞核内的积聚，并抑制致癌蛋白的翻译，导致癌细胞凋亡。人们开始认识到，针对肿瘤发生途径的小分子药物也可以具有免疫调节活性，了解这一点可以改进药物组合策略的设计。本项目旨在了解XPO1抑制如何影响NK细胞对恶性B细胞的免疫反应，以帮助设计强大的联合治疗策略来提高癌症患者的治疗水平。抑制B细胞淋巴瘤和多发性骨髓瘤细胞系以及原代慢性淋巴细胞性白血病细胞中的XPO1使癌细胞对NK细胞的细胞毒作用敏感。NK敏感性的增加在很大程度上是由于抑制NK细胞受体NKG2a的配基--人类白细胞抗原-E的表面表达减少。因此，抑制XPO1导致了NKG2A+NK细胞的主要激活，并与临床相关的单抗一起增强了抗体依赖的细胞毒性。该研究项目还发现，CLL细胞在患者的淋巴结内遇到信号，通过上调HLA-E来降低其对NK细胞激活的敏感性。总体而言，本研究项目揭示了XPO1抑制血液肿瘤的一种新的免疫调节机制，即通过破坏NKG2A：HL A-E轴使癌细胞对NK抗肿瘤功能敏感。未来的工作应探索体内NK细胞对Selinexor疗效的贡献，并研究Selinexor-NK细胞的治疗策略，以改善Selinexor的治疗结果。

Nuclear export is an important process for regulating transcription and translation by spatial distribution of transcription factors and RNA. Exportin-1 (XPO1) is a nuclear export protein that transports key tumour suppressor proteins, oncogenic mRNA and ribosomal constituents and is often dysregulated in haematological malignancies to promote cancer cell survival and proliferation. Selinexor is a first-in-class inhibitor of XPO1 and is approved for the treatment of relapsed and refractory multiple myeloma and diffuse large B cell lymphoma. Selinexor promotes accumulation of tumour suppressor proteins in the nucleus and inhibition of oncogenic protein translation leading to cancer cell apoptosis. It is beginning to be appreciated that small molecule drugs which target tumorigenic pathways can also possess immunomodulatory activity and understanding this can improve the design of drug combination strategies. This project aimed to understand how XPO1 inhibition impacts the NK cell immune response against malignant B cells to aid the design of powerful combination therapy strategies to improve the treatment of patients with cancer. XPO1 inhibition in B cell lymphoma and multiple myeloma cell lines and primary chronic lymphocytic leukaemia cells sensitised cancer cells to NK cell cytotoxicity. Increased sensitivity to NK was largely due to decreased surface expression of HLA-E, the ligand for the inhibitory NK cell receptor NKG2A. As such, XPO1 inhibition led to predominant activation of NKG2A+ NK cells and potentiated antibody-dependent cellular cytotoxicity in combination with clinically relevant monoclonal antibodies. This research project also identified that CLL cells encounter signals within the lymph nodes of patients which decreases their sensitivity to NK cell activation through upregulation of HLA-E. Overall, this research project revealed a novel immunomodulatory mechanism of XPO1 inhibition in haematological malignancies by sensitising cancer cells to NK anti-tumour functions via disruption to the NKG2A:HLA-E axis. Future work should explore the in vivo contribution of NK cells to selinexor efficacy and investigate selinexor-NK cell therapeutic strategies to improve the outcomes of selinexor treatment.