A2aR and Adenosine Pathway

Overview of A2AR and Adenosine Pathway

The naturally occurring purine nucleoside adenosine was first discovered in 1929 to influence a wide range of physiological functions. Adenosine exerts its effects by modulating 4 subtypes of specific G protein-coupled receptors (GPCRs): A1R, A2AR, A2BR, and A3R. Upon activation, A2AR and A2BR promote adenylyl cyclase (AC) activation and subsequent cyclic AMP (cAMP) production by recruiting the Gs protein, while A1R and A3R exert the opposite functions by recruiting the Gi protein. A2ARs are expressed at high levels in the striatum of the brain and immune cells and display a high affinity for adenosine. A2BRs are also widely expressed but mostly at low levels and are less sensitive to adenosine.

Researches of A2AR and Adenosine Pathway

Physiologically, the extracellular level of adenosine is very low. Pathologically, an elevated level of extracellular adenosine is specifically present in the TME and is available for tumor cells, cancer-related fibroblasts, and some immune cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), endothelial cells, and T helper cell 17 (Th17).

Upon binding to the A2AR or A2BR, adenosine triggers increased cAMP-protein kinase A signaling concomitant with immune regulation. Activation of A2AR mediates the primary immunosuppression in the TME. Several studies from different research groups found that elevated intracellular cAMP in T cells upon A2AR activation may result in T cell anergy, compromised CD8⁺ T cell infiltration, reduced levels of interleukin-2 (IL-2), tumor necrosis factor (TNFα), and interferon- (IFN-γ). The natural killer (NK) cell cytotoxicity was inhibited by this pathway as well. A2AR activation on Tregs promotes their proliferation, increases PD-1 and CTLA-4 expression, and enhances immunosuppression.

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