Adenosine impairs the proliferative capacity of terminally mature NK cells

Adenosine is a critical immunosuppressive metabolite that restricts uncontrolled activation of cytotoxic lymphocytes. However, in the tumor microenvironment adenosine impedes an active immune response. Here, we show that A2A adenosine receptor (A2AR) engagement acts as a checkpoint to limit natural killer (NK) cell maturation. Both global and NK cell-specific conditional deletion of the A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient terminally mature NK cells retained proliferative capacity and were afforded heightened reconstitution in competitive transfer assays. Targeting the A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Together, our data indicates that A2AR adenosine signaling is an intrinsic negative regulator of NK cell maturation and anti-tumor immune responses. Administration of A2AR antagonists concurrently with NK cell-based therapies may provide significant therapeutic benefit and augment NK cell-mediated anti-tumor immunity.