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, 10, 3026

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells


Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

Martin Villalba et al. Front Immunol.


The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

Keywords: CD45RARO; NK cells; antibody-dependent cell cytotoxicity (ADCC); autoimmune diseases; microenvironment; monoclonal antibodies (mAbs).


Figure 1
Figure 1
Protocols to recover/improve NK function. We describe several mechanisms to improve NK activity in patients. Naïve NK cells can be “armed” with mAbs that recognize tumor antigens (Ags) to improve their cytolytic activity against cancer cells (6). If specific mAbs against Ags of different pathogens are available, they can be used to arm NK cells to fight infections, mainly in immune compromised patients (54, 55). NK cells can be expanded (eNK) to recover NK cell functions in several diseases such as cancer, autoimmune diseases and infections (32). Treatment of patients with metabolic drugs that modify the microenvironment of the target can increase the function of both “armed” NK and eNK (25, 53). We also believe that it is possible transfer specific NK cell subsets to treat different diseases such as cancers (–13), including glioblastoma (56) that has a poor prognosis. Some NK subsets, e.x. memory NK cells could also fight infections (57) when engrafted in patients. Finally, in autoimmune diseases could be clinically relevant to replace immature CD56bright NK, which are mostly proinflammatory with mature CD56dim NK, which eliminate activated immune cells. These two NK subsets differentially express various chemokine receptors, which attract them to distinct organs (58, 59). Hence, locally playing with different chemokines should naturally facilitating the recruitment of a specific subset.

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