The role of inhibitory receptors in human NK cell function for immunotherapy

抑制性受体在人类 NK 细胞免疫治疗功能中的作用

• 批准号: 2290862
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2290862
• 关键词: role; inhibitory; receptors; human; NK

BACKGROUNDNatural Killer (NK) cells are innate effector lymphocytes that play a crucial role in viral infections and tumour immunosurveillance. NK cells directly kill target cells by releasing cytotoxic granules (e.g. granzyme B) or activating other arms of the immune system by producing a variety of cytokines and chemokines (e.g. IFN). NK cell activation is driven by multiple activatory cell surface receptors that sense an aberrant or stressful environment. Activation is also modulated by multiple inhibitory receptors.PD-1 and CTLA-4 are two inhibitory receptors, also known as immune checkpoint receptors, which have previously been identified in T cells. Upon ligand binding, these receptors reduce immune cell activation and proliferation, a process which is often hijacked by cancer cells to evade the immune system. Therefore, immune checkpoint inhibitors have been intensively researched in the context of T cells and are currently used to treat several cancers.Recent evidence suggests that PD-1 blockade therapies remain efficient even for MHC-deficient tumours, which sheds light on the importance of inhibitory receptors on NK cells. Moreover, high PD-1 cell surface expression on NK cells was observed in ovarian cancer patients, associated with poor disease prognosis. CTLA-4 has been identified on mice NK cells, but determination of its role in human NK cell activity requires further investigation. AIM OF PHD PROJECTFirstly, to generate human NK cells lacking PD-1 and CTLA-4, using lentiviral-delivered CRISPR/Cas9 genome editing methods, in order to study the effect on NK cell biology. This will then include NK cell cytotoxicity studies against a variety of target cells, and cytokine production studies upon NK cell activation. Further characterisation would involve looking at individual signalling pathways and transcriptomics. Furthermore, these modified NK cells will be tested for their enhanced function in cancer immunotherapy.

自然杀伤细胞（NK）是一种天然效应淋巴细胞，在病毒感染和肿瘤免疫监视中起着至关重要的作用。NK细胞通过释放细胞毒性颗粒（如颗粒酶B）或通过产生多种细胞因子和趋化因子（如IFN）激活免疫系统的其他分支，直接杀死靶细胞。NK细胞的激活是由多个激活的细胞表面受体驱动的，这些受体感知异常或应激环境。激活也由多个抑制受体调节。PD-1和CTLA-4是两种抑制性受体，也被称为免疫检查点受体，此前已在T细胞中发现。在配体结合后，这些受体减少免疫细胞的激活和增殖，这一过程经常被癌细胞劫持以逃避免疫系统。因此，免疫检查点抑制剂已经在T细胞的背景下进行了深入的研究，目前用于治疗几种癌症。最近的证据表明，PD-1阻断疗法即使对mhc缺陷肿瘤也有效，这揭示了抑制受体对NK细胞的重要性。此外，卵巢癌患者NK细胞上PD-1细胞表面高表达，与疾病预后不良相关。CTLA-4已在小鼠NK细胞中被鉴定，但其在人类NK细胞活性中的作用有待进一步研究。首先，利用慢病毒介导的CRISPR/Cas9基因组编辑方法，生成缺乏PD-1和CTLA-4的人NK细胞，研究其对NK细胞生物学的影响。这将包括NK细胞对各种靶细胞的细胞毒性研究，以及NK细胞活化后的细胞因子产生研究。进一步的表征将涉及观察个体信号通路和转录组学。此外，这些修饰的NK细胞将被测试其在癌症免疫治疗中的增强功能。