Abstract
Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.
Highlights
Natural Killer (NK) cells are bone marrow–derived innate lymphocytes that are found in most organs, with the largest population of NK cells residing in the blood [1]
Following CD16, NKG2D and NCR family receptor engagement adaptor proteins, DNAX-activating Protein 12 (DAP12), CD3ζ and FCRγ are rapidly phosphorylated within their immunoreceptor tyrosine-based activation motifs (ITAMs) sequences by an as yet unidentified Src-kinase, which leads to adaptor association with Spleen tyrosine kinase (Syk) or Zap70 tyrosine kinases (Figure 3B) [215,271,272]
The inhibitory signals appear to act by blocking early activation, for example, NKG2D, DNAX accessory molecule-1 (DNAM-1), 2B4, NTB-A and CD2-like receptor-activating cytotoxic cell (CRACC) all converge at Vav-1 dephosphorylation (Figure 3A), which would prevent microtubule-organizing center (MTOC) formation and result in tolerance
Summary
Natural Killer (NK) cells are bone marrow–derived innate lymphocytes that are found in most organs, with the largest population of NK cells residing in the blood [1]. Cancers 2020, 12, 952 engagement and cell killing, with receptor-ligand interactions thought to be the initiating step in the formation of an immunological synapse (IS) (Figure 1A,B) [20,21]. This is followed by recruitment of filamentous actin (F-actin) to the IS (Figure 1B) and polarization of the lytic granules and the microtubule-organizing center (MTOC) toward the class.
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