The role of checkpoint inhibitors on dendritic cells

Monoclonal antibodies (mAbs) that block checkpoint inhibitory receptors including Programmed Death (PD)-1 act directly on T cells to overcome ‘activation brakes’ induced by these immune checkpoints. Abs blocking PD-1 (pembrolizumab, nivolumab; marketed as Keytruda and Opdivo, respectively) are approved by the Therapeutic Goods Australia and the US Food and Drug Administration for the treatment of melanoma and non-small cell lung cancer with further indications of head and neck, renal, bladder cancer. These PD-1 inhibitors improve response rates, progression-free survival and overall survival in melanoma patients. Although the immunotherapy provides outstanding results in many patients, 40-60% of patients do not respond. Currently reliable biomarkers do not exist to identify potential responders to therapy. The mechanism of action of these drugs is currently attributed to T cells. Others have also clearly shown that dendritic cells (DC) are required. DC are key to antigen presentation to ‘reactivated’ T cells and are thought to be activated by dying tumour cells killed by immunotherapy-targeted T cells. However, we have now discovered that DC can express high surface levels of checkpoint inhibitors. We find that the functions of dendritic cells are themselves directly regulated by checkpoint inhibitor expression. This project will examine the molecular pathways leading to checkpoint inhibitor regulation of dendritic cell function.