Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

SIMPLE SUMMARY: Recent years marked the discovery and increased understanding of the role immune checkpoints play in immunity against cancer. This has revolutionized cancer treatment, saving the lives of many patients. For numerous years the spotlight of success has been directed towards T cells; however, it is now appreciated that other cells play vital roles in this protection. In this review we focused on cytotoxic lymphocytes Natural Killer (NK) cells, which are known to be well equipped in the fight against cancer. We explored the role of well-described and newly emerging inhibitory receptors, including immune checkpoints in regulating NK cell activity against cancer. The knowledge summarized in this review should guide the development of immunotherapies targeting inhibitory receptors with the aim of restoring NK cell responses in cancer patients. ABSTRACT: The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention.