The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Simple Summary Natural killer cells are innate cytotoxic lymphocytes that play a key role in the anti-tumor immune response. In the tumor microenvironment, however, the effector functions of these cells are often impaired by the induction of inhibitory surface molecules, including PD-1. In the present review, we provide further insight into the expression and function of the immune checkpoint PD-1 in natural killer cells, together with the limitations and perspectives of immunotherapies aimed at blocking the interaction of this inhibitory receptor with its ligands. In the last years, immunotherapy with antibodies against programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown remarkable efficacy in the treatment of different types of tumours, representing a true revolution in oncology. While its efficacy has initially been attributed only to unleashing T cell responses, responsivity to PD-1/PD-L1 blockade was observed in some tumours with low Human Leukocyte Antigen (HLA) I expression and increasing evidence has revealed PD-1 surface expression and inhibitory function also in natural killer (NK) cells. Thus, the contribution of anti-PD-1/PD-L1 therapy to the recovery of NK cell anti-tumour response has recently been appreciated. Here, we summarize the studies investigating PD-1 expression and function in NK cells, together with the limitations and perspectives of immunotherapies. A better understanding of checkpoint biology is needed to design next-generation therapeutic strategies and to improve the clinical protocols of current therapies.