Targeting a Stress-Derived Immunosuppressive Adenosine Pathway in Tumors Resistant to Checkpoint Inhibitors
Abstract
The treatment of many cancers has been affected by the use of immune therapies, improving response rates and patient outcomes. Leading the way in these cancer breakthroughs is melanoma. However, pancreatic cancer and uveal melanoma (UM), a subtype of melanoma that begins in the eye, are among those cancer types that are not responsive to immunotherapies including checkpoint inhibitors (CPIs), such as ipilimumab and pembrolizumab. Clinical response rates to ipilimumab and pembrolizumab were largely unimpressive (0 ~ 10%) with no true benefit to the overall survival of UM and pancreatic cancer patients. Other cancer types also demonstrate innate immune resistance, such as colorectal cancer, glioblastoma, and triple-negative breast cancer. There is a critical need to understand and reverse the immune resistance in metastatic UM and pancreatic cancer. Our preliminary study of the Cancer Genome Atlas data has shown that the receptor of adenosine, A2AR, was overexpressed in UM and pancreatic cancer compared with normal tissues. Moreover, high expression of CD73, an important enzyme that converts AMP to adenosine, was found to correlate with a poor survival rate of UM and pancreatic cancer patients. Importantly, multiple studies have confirmed that adenosine is an important checkpoint molecule that suppresses immunologic response and prevents associated tissue damage. Together, high levels of A2AR and CD73 in UM and pancreatic tumors indicate that the upregulation of adenosine within these tumors can lead to aberrant immune suppression. Therefore, CD73 and A2AR represent optimal targets to downregulate adenosine signaling and unlock immune suppression in UM and pancreatic cancer. In this study, we hypothesize that the CD73-Adenosine-A2AR axis represents a stress-induced immunosuppressive mechanism in UM and pancreatic cancer. This makes CD73 and A2AR promising targets to enhance the immune response in these tumors. To date, the mechanism for immune resistance driven by the CD73-Adenosine-A2AR pathway in UM and pancreatic cancer remains unknown. Clinical experience with CD73/A2AR inhibitors in UM and pancreatic cancer patients and related tumor immune signatures are not yet known. An effective immunotherapy for metastatic UM and pancreatic cancer patients is a currently unmet need. Like most immunotherapies in resistant cancers, the treatment with CPI (ipilimumab or pembrolizumab) alone may not be sufficient to promote an anti-tumor immune response. However, combining CD73/A2AR inhibitors with CPIs may overcome immune suppression and encourage the infiltration of activated cytotoxic T cells to kill a tumor. We plan to test this hypothesis with the following Specific Aims: (1) To quantify and evaluate CD73 and A2AR expressions and their clinical relevance in UM and pancreatic cancer. (2) To enhance the immune response in tumors of UM and pancreatic cancer by small inhibitors targeting CD73 and A2AR, and further examine their anti-tumor effects in combination with CPIs. From this study, we will first describe the effect of the immunosuppressive CD73-Adenosine-A2AR axis on tumor immune infiltrate and the potential benefit of targeting CD73 and A2AR to release immune suppression in UM and pancreatic cancer. We will test the novel combination of CD73/A2AR inhibitors with CPIs with regard to anti-tumor activity and immune system activation in vitro and in vivo. Upon completion of this project, we expect to identify a sensitizing immune response pattern with this combination treatment in UM and pancreatic cancer, which will provide a strong rationale for a subsequent human clinical trial. Our research identifying strategies to unlock immune suppression in a particular set of tumors with low response rates to immune therapy can have broad-reaching insights to other immune-resistant tumor types (colorectal cancer, glioblastoma, and triple-negative breast cancer), thus affecting many active duty Service members or their beneficiari
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910282
Entities
People
- Yong Qin
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army