Dissecting the roles of a novel immune-checkpoint receptor complex in driving T cell dysfunction in cancers

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Project Summary. Immune checkpoint inhibitors (ICI) have become the breakthrough therapy in the era of cancer immunotherapy. However, one of the major challenges is that the majority of patients do not respond, indicating the urgent need to identify and target non-redundant immuno-suppressive pathways. In this regard, our preliminary studies have identified a novel cross talk mechanism between two immune checkpoint proteins, namely V-domain Immunoglobulin Suppressor of T- cell Activation (VISTA) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). We hypothesize that VISTA and TIGIT form a novel co-inhibitory receptor complex that dampens T cell activation and drives T cell dysfunction. This proposal will test this hypothesis by two specific aims: First, we will perform mutagenesis studies and subject these mutants to binding and functional studies to better understand the binding epitopes and the causal link between binding and function. Lastly, we will investigate how VISTA and TIGIT drive T cell dysfunction during tumor growth in both a polyclonal and antigen specific manner. Together, these studies will warrant future studies to develop therapeutic inhibitors that block this IC receptor complex, reverse T cell dysfunction, and improve clinical outcomes in human cancers.