A 2A R eGFP reporter mouse enables elucidation of A 2A R expression dynamics during anti-tumor immune responses.

There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A _2A R receptor. Understanding of the mechanism by which A _2A R is regulated has been hindered by difficulty in identifying the cell types that express A _2A R due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A _2A R eGFP reporter mouse is developed, enabling the expression of A _2A R during ongoing anti-tumor immune responses to be assessed. This reveals that A _2A R is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4 ⁺ and CD8 ⁺ T lymphocytes and on a MHCII ^hi CD86 ^hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1 ⁺ A _2A R ^- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A _2A R and synergizes with A _2A R deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A _2A R in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.
(© 2023. The Author(s).)