Understanding immune-checkpoint inhibitory signaling by PD-1 and BTLA

A large class of receptors expressed on the surfaces of lymphocytes, the "immune checkpoints", exhibit the remarkable ability of being able to suppress their, i.e., the lymphocytes' activity. Through the use of antibodies that prevent the receptors binding their ligands, which reverses T-cell inhibition, clinical interventions via the immune checkpoints, i.e., checkpoint blockade immunotherapy, have transformed the treatment of melanoma and lung cancer, producing durable remissions in otherwise untreatable disease. Among the very small number of receptors that have been studied, a receptor known as PD-1 has emerged as the pre-eminent target for antibody blockade immunotherapy. However, anti-PD-1 antibody therapy is only effective in a fraction of cases and, very importantly, the strongest effects are observed when the anti-PD-1 antibodies are used in combination with antibodies blocking the activities of other receptors, such as CTLA-4. There are as many as 60 immune checkpoints regulating immunity, suggesting that there is extraordinary scope for broadening and improving the effectiveness of immunotherapy. However, it will not be possible to test all of these targets in the setting of clinical trials, and even less likely that they can all be tested in combination. There is, therefore, a striking need to learn more about the signaling pathways initiated by these receptors, in order to identify which combinations of targets are most likely to have synergistic effects when targeted in the clinic. There is also the deeper scientific question of why there are so many inhibitory receptors: they cannot be redundant because they would not have been preserved by evolution, but how many different ways are there to suppress a lymphocyte? In this research programme, we will start to unpick immune checkpoint signaling pathways using gene editing-based approaches in model systems, requiring familiarity with a variety of computational and quantitative tools for dissecting signaling. Our initial focus will be on a pair of receptors, PD-1 and BTLA. Although both receptors are very potent inhibitors of lymphocyte activation, antibodies that block their functions differ in their clinical efficacy. Understanding how and why these pathways differ should reveal how non-redundant inhibitory signaling is established in lymphocytes and suggest ways to improve immunotherapy.