Dual blockade of adenosine A2A and A 2B receptors is required to reverse NECA-induced immunosuppression in human macrophages: Implications for cancer immunotherapy

Adenosine receptors are a target for cancer immunotherapy, with high levels of adenosine in the tumour microenvironment producing immunosuppressive effects. Most clinical trials in cancer are targeting the A_2A adenosine receptor, but evidence suggests that both the A_2A and A_2B receptors are important for determining the effect of adenosine in myeloid-lineage cells. We therefore studied the adenosine receptors involved in mediating the effect of the adenosine analogue 5'-N-Ethylcarboxamidoadenosine (NECA) on human monocyte-derived macrophages and assessed the down-stream effect of NECA-conditioned macrophages on T cell function. NECA-conditioning of human macrophages led to changes in cytokine and chemokine production resulting in a more ‘M2’ phenotype (decreased IL-12, IL-23, IL-6, TNFa and increased VEGF-A and IL-10). NECA-conditioned macrophages altered T cell phenotype in co-culture, impairing IFNγ production. Dual blockade of both A_2A and A_2B adenosine receptors was required to reverse the cytokine and chemokine changes seen in NECA-conditioned macrophages and to recover T cell IFNγ production. These data indicate that dual A_2A/A_2B receptor blockade will be required to re-polarise macrophages in a tumour environment to support cancer immunotherapeutic approaches.