Role of CD73 - A2A/A2B receptors axis in cancer

Abstract

The adenosinergic pathway plays a critical role in cancer development and progression, as well as in drug resistance to chemotherapy and/or targeted-therapy. The goal of this PhD thesis was to investigate and fully characterize the role of CD73/adenosine A2A-A2B receptors axis in cancer, highlighting the therapeutic potential of inhibitors of the adenosinergic pathway. We firstly characterized the mechanism/s by which A2BR promotes immunosuppression and angiogenesis in tumor-bearing hosts, focusing on the role of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). The results revealed that treatment of melanoma-bearing mice with Bay60-6583, a selective A2BR agonist, is associated with 1. increased tumor VEGF-A expression and vessel density, and 2. increased accumulation of tumor-infiltrating CD11b+Gr1+cells (MDSCs). MDSCs strongly contribute to the immunosuppressive and angiogenic effects of Bay60-6583. Melanoma-bearing mice treated with a selective A2BR antagonist PSB1115 showed reduced tumor growth compared to controls and this effect was associated with reduced tumor angiogenesis, low levels of MDSCs and increased number of tumor-infiltrating CD8+ T cells. Furthermore, blockade of A2BR increased the anti-tumor effects of VEGF-A inhibitors. Next, we verified that A2BR activation also drives fibroblasts activation within melanoma tissues, by increasing the number of FAP positive cells within tumor lesions. FAP is a common marker of activated fibroblasts also named cancer-associated fibroblasts. These cells produce and secrete various tumor-promoting factors, including fibroblast growth factor (FGF)-2 and CXCL12 or stromal-derived factor 1 α (SDF1α), that were increased both in melanoma tissue and fibroblasts isolated from melanoma tissue or from skin upon Bay60-6583 treatment. Bay60-6583-induced FGF-2 from fibroblasts contributed to melanoma cells proliferation. The CXCL12/CXCR4 pathway, instead, was involved in the pro-angiogenic effects of A2BR agonist, but not in its immunosuppressive effects. These effects were significantly blocked by the A2BR antagonists PSB1115. Taken together, these data elucidate the pivotal role of A2BR in establishing a positive cross-talk between tumor-infiltrating immune cells, fibroblasts and endothelial cells that sustain tumor growth, reinforcing the therapeutic potential of A2BR blockers for cancer therapy. ... [edited by Author]