Immune cells use a molecular braking system called "checkpoints," and when antibodies block one of these brakes—the receptor TIGIT—they can revive the immune system's attack on tumours. But this treatment works only in a minority of patients, and often triggers severe side effects. The problem is that scientists do not understand exactly how these checkpoints work at the scale of individual molecules. The researcher has discovered that when TIGIT is activated, it physically clusters within nanometres of the T cell receptor—the molecule that triggers an immune response. This close proximity appears to be critical for both the checkpoint's normal function and for antibody drugs to work effectively. This project will map how this nanoscale proximity drives different immune responses in various cell types, test whether other checkpoints also require this close positioning, and determine how therapeutic antibodies exploit these interactions. If successful, this fundamental science could reveal why checkpoint-blocking drugs fail in most patients and suggest new ways to design antibodies that work more reliably—potentially improving cancer immunotherapy without the guesswork that currently limits its use.
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Antibodies blocking immune checkpoint receptors, such as TIGIT, can revive anti-tumour immunity. Yet, effective responses remain infrequent, whilst severe immune-related side effects are frequent. Precisely how immune checkpoints regulate immune responses remains a significant knowledge gap, preventing optimisation of therapeutic strategies and the identification of biomarkers for patient selection and treatment response. The nanoscale arrangement of immunoreceptors and their signalling machinery is critical to the outcomes of cellular interactions. I recently demonstrated that upon ligation TIGIT reorganises to cluster within nanometres of the T cell receptor (TCR). Moreover, I observe similar nano-organisation when blocking antibodies bind both TIGIT on T cells and Fc receptors on interacting antigen-presenting cells. This observation is significant as effective TIGIT blockade requires Fc receptor interactions. Thus, I hypothesise that the nanoscale proximity of immune checkpoints to stimulatory receptors is essential for both physiological inhibition and therapeutic blockade and that modulating their relative localisation represents an innovative therapeutic strategy. Using TIGIT as a focus, I will (i) define how proximal inhibitory signalling drives diverse phenotypes in different immune subsets, (ii) determine whether proximity to stimulatory receptors is a general requirement for immune checkpoint inhibition and (iii) define Fc-mediated interactions promoting anti-tumour immunity by immune checkpoint antibodies.
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