Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Adenosine receptors are a family of G-coupled receptors which mediate the anti-inflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A2B receptor in regulating tumor progression and discuss the development of A2B receptor inhibitors as potential therapeutic agents in cancer treatment.