A New Immune Checkpoint Pathway in Human Bladder Cancer

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A new immune checkpoint pathway in human bladder cancer This proposal is in response to the PAR-19-183 (Biology of Bladder Cancer). Bladder cancer is one of the most common malignancies in the United States. The survival rate of bladder cancer has been largely unchanged for the last 30 years. Very recently PD-1/PD-L1 inhibitors were approved by FDA for the treatment of patients with metastatic bladder cancer, but worked in only a subset of ~15-25% of patients. Thus, there is a pressing need to develop new and effective treatment for bladder cancer. Developing novel checkpoint inhibitors, especially inhibitors that target outside the PD1/PD-L1 and CTLA-4 pathways, is a promising strategy and may potentially have high impact in clinical management of human bladder cancer. Our central hypothesis of this proposal is that KIR3DL3-HHLA2 is a previously unrecognized immunosuppressive pathway as well as a novel therapeutic target in human bladder cancer. Guided by our published clinical and basic research and our strong preliminary data, we will pursue following specific aims: 1) Investigate the cellular and molecular mechanisms of HHLA2 expression in human bladder cancer and APCs; 2) Dissect co-inhibitory function and signaling of the KIR3DL3-HHLA2 pathway; and 3) Develop new immunotherapies against human bladder cancer by targeting the KIR3DL3-HHLA2 pathway. This proposal comprises an integrated network of multi-disciplinary collaborative investigators (immunologists, urologists, oncologists, and bioinformaticians) to accelerate translational research and maximize future clinical benefits. The outcomes of this project will reveal new fundamental biology of human bladder cancer and will guide the rational development of new immunotherapies for the treatment of human bladder cancer.