Abstract
During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.
Highlights
Throughout evolution, innate immunity evolves earlier than adaptive immunity and is decisive for its exceptional line of defence in host immunity [1]
natural killer (NK) cells express a balance of germ-line-encoded activation receptors, which consist of natural cytotoxicity receptors (NCRs) such as NKp80, NKp46, NKp44, NKp30, and others; the c-type lectins, a superfamily of proteins that recognize a broad range of repertoire of ligands, such as NKG2D, Cancers 2020, 12, 1807; doi:10.3390/cancers12071807
Mechanisms cells propagate their immune response through a complex cascade of receptors, and various strategies of NK cell activation are under consideration, including antibody cross-linking, soluble ligands, NK cells propagate their immune response through a complex cascade of receptors, and various and monoclonal antibodies, such as targeting NKG2D [17] and NKp30 [18], stimulated dimierized soluble strategies
Summary
Throughout evolution, innate immunity evolves earlier than adaptive immunity and is decisive for its exceptional line of defence in host immunity [1]. NK cells express a balance of germ-line-encoded activation receptors, which consist of natural cytotoxicity receptors (NCRs) such as NKp80, NKp46, NKp44, NKp30, and others; the c-type lectins, a superfamily of proteins that recognize a broad range of repertoire of ligands, such as NKG2D, Cancers 2020, 12, 1807; doi:10.3390/cancers12071807 www.mdpi.com/journal/cancers domains, among others (Figure 2) [11] Under malignant conditions, such as healthy cells transforming into cancer cells, stress ligands upregulate and cognately bind and activate NK receptors (Figure 2A). NK cells target malignant cells through an array of mechanisms Despite these mechanisms, the malignant cells can evolve various escape routes, such as downregulation of adhesion molecules, a cognate ligand for activating receptors, or upregulation of major histocompatibility complex (MHC) molecules and secretion ofsome immunosuppressive cytokines such asinterleukin-10 (IL-10), transforming growth factor-β (TGF-β), and indoleamine. II molceules (MHC-II), natural cytotoxicity receptors (NCRs), tumor necrosis factor-alpha (TNF-α))
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