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Targeting a Stress-Derived Immunosuppressive Adenosine Pathway in Tumors Resistant to Checkpoint Inhibitors
Immunotherapies largely ineffective in uveal melanoma (UM) and pancreatic ductal adenocarcinoma (PDAC). The mechanisms underlying poor response to immunotherapy in UM and PDAC are unclear. Our preliminary analysis showed that A2AR and CD73 were overexpressed in UM and PDAC and associated with poor survival. CD73 and A2AR are crucial factors in the immunosuppressive adenosine pathway. A major gap lies in our knowledge of the role of the adenosine pathway driving immune suppression in UM and PDAC. In this proposal, we hypothesize that the CD73-Adenosine-A2AR axis represents a stress-induced immunosuppressive mechanism in UM and PDAC. The overall goal of this proposal is to analyze the functional roles of CD73 and A2AR in the immunosuppressive microenvironment of UM and PDAC. Furthermore, we will develop a new strategy combining CD73/A2AR inhibitors with checkpoint inhibitors to inhibit UM and PDAC tumor growths. This preclinical translational research will help to establish CD73 and A2AR as novel biomarkers and immunotherapy targets for metastatic UM and PDAC.
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