AR eGFP Reporter Mouse Enables Elucidation of AR 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 AR receptor. Understanding of the mechanism by which AR is regulated has been hindered by difficulty in identifying the cell types that express AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an AR eGFP reporter mouse is developed, enabling the expression of AR during ongoing anti-tumor immune responses to be assessed. This reveals that AR 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 MHCIICD86 subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1AR cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates AR and synergizes with AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.