Targeting a Stress-Derived Immunosuppressive Adenosine Pathway in Tumors Resistant to Checkpoint Inhibitors

Pancreatic ductal adenocarcinoma PDAC and uveal melanoma UM, a subtype of melanoma that begins in the eye, are not responsive to immune checkpoint inhibitors CPIs, such as ipilimumab or pembrolizumab. The accumulation of adenosine in the tumor microenvironment acts as a negative regulator for both the activation and effector phases of the anti-tumor T cell response. It is known that CD73 and A2AR are crucial factors in the immunosuppressive adenosine pathway. Up till now, a major gap lies in our knowledge of the role of adenosine pathway driving immune suppression in UM and PDAC. In this study, we will investigate a new mechanism for immune resistance driven by aberrant adenosine signaling by analyzing the immune profiles of UM and PDAC tumors relevant to CD73 and A2AR. We will also attempt to demonstrate how blockade of CD73 and A2AR to reverse the immunosuppressive tumor microenvironment. Furthermore, we will explore the strategy of combining CD73A2AR inhibitors with immune checkpoint blockade anti-PD-1 therapy to overcome the immune resistance of UM and PDAC.