The nanoscale governance of immune checkpoint receptors

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.