The Roles of a Novel Immune-Checkpoint Receptor Complex in Driving T Cell Dysfunction in Cancer

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Summary Immune checkpoint inhibitors (ICI) have become the breakthrough therapy in the era of cancer immunotherapy. However, one of the major challenges is that majority of patients do not respond, indicating the urgent need to identify and target non-redundant immunosuppressive pathways. Our preliminary studies have identified a novel cross-talk mechanism between two immune checkpoint receptors. We hypothesize that this novel cross-talk mechanism drives T cell exhaustion and impair anti-tumor immune response. We will test this hypothesis by two specific aims: in Aim 1, we will determine the causal relationship between receptor binding and the inhibitory effects on T cell activation. In Aim 2, we will investigate how this novel cross-talk mechanism drives T cell exhaustion and whether blocking this axis can enhance T cell-mediated anti-tumor immunity. Together, these studies will guide future studies to target this novel axis, reverse T cell exhaustion, and improve clinical outcomes in cancer patients.