Unpicking the Immune Checkpoints

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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.