ADORA2A gene encodes a protein which is one of receptor subtypes for adenosine, abundant in basal ganglia or vasculature. Adenosine signaling plays an important role in inflammation and the immune response. Many cells in the tumor microenvironment express ectopic CD39 and CD73, leading to the buildup of extracellular adenosine. Engagement of adenosine with the high affinity A2a receptor (A2aR) on the surface of T cells, macrophages, NK cells, neutrophils, and dendritic cells causes downregulation of the immune response.
Several A2aR antagonists have progressed to clinical trials for the treatment of Parkinson’s disease, and preclinical studies have confirmed that blockade of A2a receptor activation has the ability to markedly enhance anti-tumor immunity. Mice treated with A2aR antagonists show significantly delayed tumor growth, and A2aR knockout mice demonstrate increased tumor rejection. Most promising, A2aR blockade can be used in synergy with the inhibition of other immune checkpoint pathways. Studies show that the combination of A2aR blockade and PD-1 inhibition is more effective than either treatment separately. A2aR blockade increases the activity of CTLA-4 and TIM-3 inhibition in controlling the growth of CD73+ melanoma. ADORA2A is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium.