NK cells for PD-1/PD-L1 blockade immunotherapy: pinning down the NK cell

Abstract

In spite of a very robust body of literature and definitive data demonstrating the importance of the programmed cell death receptor-1 (PD-1) pathway in T cells and their function, the data on NK cell PD-1 expression have been highly variable and, particularly in the case of mouse NK cells, scarce. In this issue of the JCI, Hsu et al. present data demonstrating PD-1 expression on mouse NK cells only within tumors and show that PD-1 blockade elicits an antitumor NK cell-mediated response. This study indicates that, given the complexity of both the biology and study of NK cells, further work is needed to more clearly determine the role of the PD-1/PD-1 ligand (PD-L1) on NK cells.

Figure 1. The role of NK cells in checkpoint blockade.

(A) Inflammatory host disease environments affect PD-1 expression on NK cells. Hsu et al. show upregulation of PD-1 expression in the tumor microenvironment. The signals that determine PD-1 expression on NK cells are not completely understood. Checkpoint blockade could activate NK cells by preventing inhibition mediated by PD-L1⁺ target cells. (B) The activity of NK cells is determined by an array of activating and inhibitory signals, only a small selection of which are shown here. Antibody blockade of PD-1 would prevent cell-intrinsic inhibitory signaling. Antibody blockade of PD-L1 would also prevent cell-intrinsic signaling and, additionally, prevent NK cells from sending an inhibitory signal to PD-1⁺ T cells and/or PD-L1⁺ antigen-presenting cells (DCs).