Grant: Foundation Grant

T-cells of the immune system recognize and eliminate foreign pathogens. Over the past decade, it has become clear that the same cells can recognize and kill tumor cells responsible for cancer. T-cells express stimulatory and inhibitory receptors that determine how they will respond to tumors. Positive receptors include the T-cell receptor (TCR) and a co-receptor called CD28, while inhibitory co-receptors CTLA-4 and PD-1 reduce T-cell responses. Blockade of these inhibitory co-receptors with antibodies in 'immune checkpoint blockade" (ICB) and the generation of chimeric antigen receptors (CARs) in immunotherapy has now revolutionized the treatment of cancer patients with unprecedented response rates against certain tumors. Despite this success, most patients are not cured, and some cancers are unresponsive. New modalities will depend on an understanding of the make-up of signaling pathways in T-cells engaged by receptors on their cell surface. This grant proposes to discover new pathways that regulate specific T-cells, to uncover how they operate mechanistically and to apply this knowledge to the development of new immunotherapies against cancer. We propose to take a multipronged approach by uncovering the signaling mechanism used by T-cell co-receptors to promote anti-tumor immunity, to 'stop or arrest' T-cells in tumors so that they accumulate to kill the tumor and to block the expression of inhibitory PD-1 and CTLA-4 with small molecules that have therapeutic advantages over present therapies.