A critical mechanism of cancer immune evasion is the generation of high levels of immunosuppressive adenosine via the purinergic pathway within the tumor microenvironment.
Extracellular adenosine has a marked dampening effect on the immune response, suppressing effector cell function and stabilizing immunosuppressive regulatory cells.
Adenosine’s role in immune suppression is corroborated by observations that the TME has significantly elevated concentrations (100-500 fold) of extracellular adenosine.
Upon engagement of the A2A or A2B receptors, adenosine triggers increased adenylyl cyclase activity with concomitant increases in intracellular cAMP resulting in profound dampening of the immune response – a fundamental mechanism of cancer immune evasion.
Over-expression of A2AR and A2BR leads to poor prognosis in multiple cancers. Furthermore, genetic ablation of A2AR and A2BR leads to spontaneous regression of established tumors.
Accordingly, it is a high priority target for immunotherapeutic intervention.