All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity

Abstract

NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences.

Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+ NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer

“…NK cell-mediated killing is mainly mediated by cytotoxic granules, such as perforin, granzymes, and granulysin, which are degranulated to initiate programmed target cell death or by death ligands, such as FasL and TRAIL, to further enhance target cell killing. The most recent findings suggest that NK cells are not only responsible for the non-inflammatory programmed cell death but also induce the immunological and more relevant inflammatory cell death, which triggers the release of “danger-associated molecular patterns” (DAMPs) and tumor antigens, which stimulate the adaptive immune system [ 30 ]. In contrast to CD8+ cytotoxic T cells that share the killing mechanisms mentioned above, NK cells are able to kill target cells via a unique mechanism termed antibody-dependent cellular cytotoxicity (ADCC), which is mediated by the low-affinity Fc gamma receptor CD16.…”

Antitumor effects of polysaccharides from Tetrastigma hemsleyanum Diels et Gilg via regulation of intestinal flora and enhancing immunomodulatory effects in vivo

“…Coincidentally, relevant studies have also shown that polysaccharides can promote the phagocytosis of monocyte macrophages and have certain immunomodulatory activity, which is consistent with our study results ( 64 ). NK-cell activity is also an important indicator of the nonspecific immune system ( 65 ). The results showed that THP can enhance the activity of NK cells to regulate the body’s immunity, and can be used as an effective therapy to improve the immunodeficiency.…”

Crosstalk Between NK Cell Receptors and Tumor Membrane Hsp70‐Derived Peptide: A Combined Computational and Experimental Study

“…[ 8 ] NK cell activation and target cell engagement induce direct cancer cell death by different mechanisms including cytotoxic granule and death receptor‐mediated cell lysis as well as enabling complement‐ and/or antibody‐dependent cell‐mediated cytotoxicity (ADCC). [ 9 ] Moreover, activated NK cells can produce an array of immunoregulatory cytokines and chemokines to recruit immune cells into the tumor microenvironment and thereby further amplify and orchestrate the immune response. [ 10 ] Accompanied by receptor‐priming signals, the initial anti‐tumor response elicited by NK cells is supported by adaptive immune cells through contact and paracrine/exocrine signaling.…”