Investigation into th NK cell Immunomodulatory activity of XP01 inhibitors

核输出是通过转录因子和RNA的空间分布调控转录和翻译的重要过程。Exportin-1 （XPO1）是一种核输出蛋白，可运输关键的肿瘤抑制蛋白、致癌mRNA和核糖体成分，在血液学恶性肿瘤中经常失调，以促进癌细胞的存活和增殖。Selinexor是XPO1的一流抑制剂，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促进细胞核中肿瘤抑制蛋白的积累，抑制致癌蛋白的翻译，导致癌细胞凋亡。人们开始认识到靶向致瘤途径的小分子药物也可以具有免疫调节活性，了解这一点可以改善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，改善癌症患者的治疗。B细胞淋巴瘤和多发性骨髓瘤细胞系以及原发性慢性淋巴细胞白血病细胞中的XPO1抑制使癌细胞对NK细胞的细胞毒性敏感。对NK的敏感性增加主要是由于抑制NK细胞受体NKG2A的配体HLA-E的表面表达减少。因此，XPO1抑制导致NKG2A+ NK细胞的显性活化，并与临床相关的单克隆抗体联合增强抗体依赖性细胞毒性。本研究项目还发现CLL细胞在患者淋巴结内遇到信号，通过上调HLA-E降低其对NK细胞活化的敏感性。总体而言，本研究项目揭示了XPO1抑制血液学恶性肿瘤的一种新的免疫调节机制，即通过破坏NKG2A:HLA-E轴使癌细胞对NK抗肿瘤功能敏感。未来的工作应该探索NK细胞对selinexor疗效的体内贡献，并研究selinexor-NK细胞治疗策略，以改善selinexor治疗的结果。

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.