Unpicking the Immune Checkpoints

我实验室的首要目标是试图了解免疫系统是如何在分子水平上受到调节的。免疫系统由血液中的一组称为白细胞或淋巴细胞的细胞组成，这些细胞在其表面表达大量称为受体的蛋白质。细胞表面受体是任何类型的细胞获知外部发生的事件的途径。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。淋巴细胞表达的最重要的受体是所谓的“免疫检查点”受体，它限制了淋巴细胞对这些外部信号的反应程度。在一个特殊的例子中，用基于抗体的药物阻断PD-1受体的活性具有激活淋巴细胞的效果，在癌症的情况下，淋巴细胞可以导致针对肿瘤的治愈性免疫反应。像这样的发现正开始改变医学。问题是，我们对免疫检查点受体如何限制淋巴细胞的活动知之甚少，也就是说，它们启动了什么细胞内信号传导途径。这样的受体数量很多（60-70个），它们似乎不太可能做同样的事情，因为它们不可能在这么多动物物种的进化中被保存下来。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为主要例子之一，但我们也将与其他重要的受体TIGIT和BTLA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（例如，阻断抗体）以实现最佳临床结果。我们的方法是了解免疫检查点受体水平的干预如何根据疾病（即组织背景）产生截然不同的结果。

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.