Targeting a Stress-Derived Immunosuppressive Adenosine Pathway in Tumors Resistant to Checkpoint Inhibitors
Abstract
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 CD73/A2AR inhibitors with immune checkpoint blockade (anti-PD-1 therapy) to overcome the immune resistance of UM and PDAC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1104220
Entities
People
- Yong Qin
Organizations
- University of Texas at Austin