Unpicking the Immune Checkpoints

解开免疫检查点

• 批准号: MR/Y015355/1
• 负责人: Simon Davis
• 金额: $ 177.29万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY015355%2F1
• 关键词: Unpicking; Immune; Checkpoints

The over-riding goal of my laboratory is to try to understand how the immune system is regulated at the molecular level. The immune system comprises the set of cells in the blood called white blood cells or lymphocytes, which express large numbers of proteins on their surfaces, called receptors. Cell surface receptors are the means by which any type of cell is informed of events occurring outside it. In the case of lymphocytes, the important external event is an infection, or the formation of a tumour. Among the most important of the receptors expressed by lymphocytes are the so-called "immune checkpoint" receptors, which limit the extent to which the lymphocytes respond to these external cues. In one particular example, blocking the activity of a receptor called PD-1 with antibody-based drugs has the effect of activating the lymphocyte, which, in the setting of cancer, can lead to curative immune responses against tumours. Discoveries like this are beginning to transform medicine. The problem is that we know very little about how the immune checkpoint receptors limit the activities of lymphocytes, i.e., what pathways of intracellular signaling they initiate. There is a large number of these receptors (60-70), and it seems very unlikely they do the same thing because they wouldn't have been preserved by evolution in so many animal species. Using gene-editing approaches, we propose to interrogate the ways in which the immune checkpoints exert their effects in lymphocytes, taking PD-1 as one of our key examples, but we will also be making comparisons with other important receptors called TIGIT and BTLA. Our objectives are to understand why there are so many immune checkpoint receptors, and to determine how best to combine therapeutic interventions (with, e.g., blocking antibodies) to achieve the best clinical outcomes. Our approach is to understand how interventions at the level of the immune checkpoint receptors can have profoundly different outcomes depending on disease - i.e., tissue - contexts.

我实验室的过度目标是试图了解如何在分子水平调节免疫系统。免疫系统包括称为白细胞或淋巴细胞的血液中的一组细胞，这些细胞在其表面上表达大量蛋白质，称为受体。细胞表面受体是将任何类型的细胞内部事件告知其外部事件的手段。在淋巴细胞的情况下，重要的外部事件是感染或肿瘤的形成。在淋巴细胞表达的最重要的受体中，是所谓的“免疫检查点”受体，它限制了淋巴细胞对这些外部提示的反应程度。在一个特定的例子中，用基于抗体的药物阻断称为PD-1的受体的活性具有激活淋巴细胞的作用，在癌症的情况下，淋巴细胞可以导致针对肿瘤的治疗免疫反应。这样的发现开始改变医学。问题在于，我们对免疫检查点受体如何限制淋巴细胞的活性，即它们启动的细胞内信号的途径几乎没有了解。这些受体中有很大一部分（60-70），而且似乎不太可能做同样的事情，因为在这么多动物物种中，它们不会被进化保存。使用基因编辑方法，我们建议询问免疫检查点在淋巴细胞中发挥作用的方式，以PD-1作为我们的关键例子之一，但我们还将与其他称为Tigit和Btla的重要受体进行比较。我们的目标是了解为什么有这么多免疫检查点受体，并确定如何最好地结合治疗干预措施（例如阻断抗体）以实现最佳的临床结果。我们的方法是了解免疫检查点受体水平上的干预措施如何取决于疾病（即组织 - 环境）的结果。