NK Cell Dysfunction and Checkpoint Immunotherapy

Abstract

NK cells play important roles in the innate immune responses against tumors. The effector function of NK cells relies on the integration of activating and inhibitory signals. Emerging checkpoint receptors and molecules are being revealed to mediate NK cell dysfunction in the tumor microenvironment. Inhibition of some NK cell surface checkpoint receptors has displayed the potential to reverse NK cell dysfunction in tumors, and to boost anti-tumor immunity, both in clinical trials (anti-KIR and anti-NKG2A), and in preclinical studies (e.g., anti-TIGIT, and anti-CD96). To fully exploit the potential of NK-based checkpoint immunotherapy, more understanding of the regional features of NK cells in the tumor microenvironment is required. This will provide valuable information regarding the dynamic nature of NK cell immune response against tumors, as well as novel checkpoints or pathways to be targeted. In this Review, we discuss recent advances in the understanding of NK cell dysfunction in tumors, as well as emerging strategies of NK-based checkpoint immunotherapy for tumors.

Keywords: checkpoint blockade; immune evasion; immune tolerance; inhibitory receptors; regional immunity.

Figure 1

Targeting NK cell dysfunction via checkpoint inhibition tumor immunotherapies. NK cells display a dysfunctional status in tumors, along with detrimental upregulation of some checkpoint molecules (e.g., TIGIT, CD96, PD-1, and FBP1). These molecules, as well as other constitutively expressed checkpoint molecules (e.g., KIRs, NKG2A, A2AR, and IL-1R8), functions to impair the anti-tumor effector potentials of NK cells in tumors. These checkpoint molecules represent potential targets for NK–based immunotherapy. Therapeutically targeting these molecules by blocking monoclonal antibodies or small molecule inhibitors might unleash NK cells from those immune suppressive mechanisms, and boost NK cell anti-tumor activity. Antibody and inhibitor symbols in light color (those for CIS and IL-1R8) indicate that the agents have not been developed yet.