Targeting natural killer cell receptors for immunotherapeutic benefit

肝细胞癌（HCC）起源于肝脏，是世界上第五大常见癌症，也是第三大癌症死亡原因。在世界范围内，它是在病毒性肝炎的背景下出现的，但由于与肥胖有关的非酒精性脂肪性肝病患者数量的增加，其在英国的患病率正在上升。它仍然难以治疗，部分原因是它发生在通常被肝硬化破坏的肝脏中，这意味着患者对化疗药物的耐受性很差。此外，患者出现在疾病的晚期，超过了治愈性手术治疗的时间。这些患者的前景很差，因此需要更新的治疗方法。自然杀伤细胞（NK）是先天免疫系统的细胞，具有抗癌特性，肝脏是NK细胞聚集的器官。因此，我们提出NK细胞是HCC的潜在治疗方法。NK细胞靶向治疗目前正在进行大量的研究，但往往是繁琐和昂贵的。我们最近的工作表明，一种涉及疫苗接种的新型治疗策略可能是开发更好的NK细胞靶向策略的一种选择。我们建议使用一种DNA疫苗，该疫苗编码一种蛋白质的序列，我们之前的工作表明这种蛋白质被NK细胞受体KIR2DS2识别。我们将首先优化递送DNA疫苗的程序。DNA疫苗随后将在临床前模型中进行测试，以确定其作为治疗药物的潜力，重点关注HCC作为治疗靶点。作为该项目的一部分，我们还将测试NK细胞以类似于另一种免疫细胞（细胞毒性T细胞）的方式识别肿瘤抗原的新概念。这些细胞识别被称为MHC I类分子的特殊蛋白质显示在细胞表面的细胞蛋白质的小片段。我们正在进行的工作表明，一种来自蛋白质XPO1的小肽，通过结合MHC I类和KIR2DS2，然后激活NK细胞，是NK细胞的潜在靶标。XPO1蛋白在包括肝细胞癌在内的许多癌症中上调。因此，我们认为这为我们的NK细胞治疗HCC提供了理论依据。我们将进行体外和体内实验来验证KIR2DS2+ NK细胞将XPO1识别为肿瘤抗原的假设。我们的工作测试了NK细胞治疗的新策略，该策略对HCC和其他癌症具有潜在的转化和临床益处。我们相信，无论是作为单一疗法，还是与目前可用的免疫治疗策略相结合，它都将具有广泛的适用性。

Hepatocellular carcinoma (HCC) arises in the liver, is the fifth most common cancer worldwide and the third commonest cause of cancer death. On a worldwide basis it arises on the background of viral hepatitis, but its prevalence is increasing in the UK due to the rise in numbers of people with non-alcoholic fatty liver disease, which is associated with obesity. It remains difficult to treat, in part because it arises in livers that are usually damaged by cirrhosis, which means that chemotherapeutic agents are poorly tolerated by patients. Furthermore, patients present in advanced stages of disease beyond the time when curative surgical treatment is possible. The outlook for these patients is poor and therefore newer therapies are needed. Natural killer (NK) cells are cells of the innate immune system which have anti-cancer properties and the liver is an organ where NK cells accumulate. We therefore propose that NK cells are a potential therapeutic for HCC. NK cell targeting therapies are currently undergoing much investigation, but are often cumbersome and expensive. Our recent work has suggested that a novel therapeutic strategy involving vaccination, might be an option for developing better NK cell targeting strategies. We propose using a DNA vaccine that encodes a sequence for a protein that our previous work has shown is recognised by the NK cell receptor KIR2DS2. We will first optimise the procedure for delivering this DNA vaccine. The DNA vaccine will then be tested in preclinical models to determine their potential as therapeutics, focussing on HCC as the therapeutic target. As part of this project we will also test the novel concept that NK cells can recognise tumour antigens in a similar way to another immune cell, the cytotoxic T cell. These cells recognise small fragments of cellular proteins which are displayed on the cell surface by specialised proteins called MHC class I molecules, Our on-going work shows that one small peptide, derived from the protein XPO1, is a potential target for NK cells by binding MHC class I and KIR2DS2 and then activating NK cells. The XPO1 protein is upregulated in many cancers including hepatocellular carcinoma. We therefore consider that it provides a rationale for our NK cell therapy of HCC. We will perform in vitro and in vivo experiments to test the hypothesis that KIR2DS2+ NK cells recognise XPO1 as a tumour antigen. Our work tests a novel strategy for NK cell therapy, which has potential translational and clinical benefit for HCC, and for other cancers. We believe it would have wide applicability as both a monotherapy and in conjunction with currently available immunotherapeutic strategies.