Targeting natural killer cell receptors for immunotherapeutic benefit

靶向自然杀伤细胞受体以获得免疫治疗益处

• 批准号: MR/S009388/1
• 负责人: Salim Khakoo
• 金额: $ 62.44万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS009388%2F1
• 关键词: Targeting; natural; killer; cell; receptors

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.

肝细胞癌（HCC）发生在肝脏中，是全球第五大常见癌症，也是第三大常见癌症死亡原因。在全球范围内，它是在病毒性肝炎的背景下出现的，但由于与肥胖相关的非酒精性脂肪肝患者数量的增加，其在英国的患病率正在增加。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，超过了可能进行根治性手术治疗的时间。这些患者的前景很差，因此需要更新的治疗方法。自然杀伤（NK）细胞是具有抗癌特性的先天免疫系统的细胞，并且肝脏是NK细胞积聚的器官。因此，我们认为NK细胞是一种潜在的治疗肝癌的方法。NK细胞靶向疗法目前正在进行大量研究，但通常繁琐且昂贵。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，它编码一种蛋白质的序列，我们以前的工作已经表明这种蛋白质可以被NK细胞受体KIR2DS2识别。我们将首先优化提供这种DNA疫苗的程序。然后将在临床前模型中测试DNA疫苗，以确定其作为治疗剂的潜力，重点是HCC作为治疗靶点。作为该项目的一部分，我们还将测试新的概念，即NK细胞可以以与另一种免疫细胞（细胞毒性T细胞）类似的方式识别肿瘤抗原。这些细胞识别通过称为MHC I类分子的专门蛋白质展示在细胞表面上的细胞蛋白质的小片段。我们正在进行的工作表明，来自蛋白质XPO 1的一种小肽是NK细胞的潜在靶点，其通过结合MHC I类和KIR 2DS 2然后激活NK细胞。XPO 1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提供了理论基础。我们将进行体外和体内实验，以检验KIR2DS2+ NK细胞将XPO 1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。我们相信它将具有广泛的适用性，作为单一疗法和与目前可用的免疫策略相结合。

项目成果

Selinexor Enhances NK Cell Activation Against Malignant B Cells via Downregulation of HLA-E.

• DOI: 10.3389/fonc.2021.785635
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Fisher JG;Walker CJ;Doyle AD;Johnson PW;Forconi F;Cragg MS;Landesman Y;Khakoo SI;Blunt MD
• 通讯作者: Blunt MD

KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity.

• DOI: 10.4049/jimmunol.2101139
• 发表时间: 2022-07-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Blunt MD;Vallejo Pulido A;Fisher JG;Graham LV;Doyle ADP;Fulton R;Carter MJ;Polak M;Johnson PWM;Cragg MS;Forconi F;Khakoo SI
• 通讯作者: Khakoo SI

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.

• DOI: 10.1038/s41375-023-01984-z
• 发表时间: 2023-10
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Fisher, Jack G.;Doyle, Amber D. P.;Graham, Lara V.;Sonar, Shreyanshi;Sale, Ben;Henderson, Isla;Del Rio, Luis;Johnson, Peter W. M.;Landesman, Yosef;Cragg, Mark S.;Forconi, Francesco;Walker, Christopher J.;Khakoo, Salim. I.;Blunt, Matthew D.
• 通讯作者: Blunt, Matthew D.

Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade.

• DOI: 10.3389/fimmu.2021.643310
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Bozward AG;Warricker F;Oo YH;Khakoo SI
• 通讯作者: Khakoo SI

MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges.

• DOI: 10.3390/cancers16020259
• 发表时间: 2024-01-06
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Phoolchund, Anju G. S.;Khakoo, Salim I.
• 通讯作者: Khakoo, Salim I.