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Review
. 2021 Oct 27:12:765705.
doi: 10.3389/fimmu.2021.765705. eCollection 2021.

Making a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies

Samantha A Barnes  1   2 , Isabella Trew  1   2 , Emma de Jong  1 , Bree Foley  1
Affiliations
Review

Making a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies

Samantha A Barnes et al. Front Immunol. .

Abstract

Over the past 20 years natural killer (NK) cell-based immunotherapies have emerged as a safe and effective treatment option for patients with relapsed or refractory leukemia. Unlike T cell-based therapies, NK cells harbor an innate capacity to eliminate malignant cells without prior sensitization and can be adoptively transferred between individuals without the need for extensive HLA matching. A wide variety of therapeutic NK cell sources are currently being investigated clinically, including allogeneic donor-derived NK cells, stem cell-derived NK cells and NK cell lines. However, it is becoming increasingly clear that not all NK cells are endowed with the same antitumor potential. Despite advances in techniques to enhance NK cell cytotoxicity and persistence, the initial identification and utilization of highly functional NK cells remains essential to ensure the future success of adoptive NK cell therapies. Indeed, little consideration has been given to the identification and selection of donors who harbor NK cells with potent antitumor activity. In this regard, there is currently no standard donor selection criteria for adoptive NK cell therapy. Here, we review our current understanding of the factors which govern NK cell functional fate, and propose a paradigm shift away from traditional phenotypic characterization of NK cell subsets towards a functional profile based on molecular and metabolic characteristics. We also discuss previous selection models for NK cell-based immunotherapies and highlight important considerations for the selection of optimal NK cell donors for future adoptive cell therapies.

Keywords: cancer immunotherapy; cell metabolism; donor selection; epigenetics; natural killer cells; phenotype; transcriptomics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
NK Cells Exert a Range of Direct and Indirect Antitumor Effects. NK cell activation is governed by the net balance between signals received through various activating and inhibitory NK cell receptors. When the balance is tipped towards activation, NK cells can directly lyse target cells through release of the preformed cytotoxic granules granzyme B and perforin (natural killing) or by the engagement of target cell death receptors by NK cell-expressed death receptor ligands TRAIL and FasL (death receptor pathway). Antibody opsonized target cells may also be directly lysed through engagement of the NK cell IgG Fc region receptor III (FcγRIII; CD16) in a process of antibody dependent cell-mediated cytotoxicity (ADCC). Activated NK cells are also potent producers of immunomodulatory cytokines (such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF)) and chemokines (including interleukin-8 (IL-8), CCL5, and XCL1) which activate and recruit other immune cells to the tumor microenvironment, indirectly driving a multifaceted antitumor response. Created with (Biorender.com).
Figure 2
Figure 2
Models of NK Cell Alloreactivity Based on KIR and HLA Expression. Donor NK cells maintain tolerance to self through interactions between inhibitory killer immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) ligands expressed on healthy autologous cells. In the context of haploidentical HSCT, interactions between donor and recipient KIR and HLA mediate NK cell alloreactivity against target cells. Three models have been described which predict NK cell alloreactivity: mismatch between the donor and recipient HLA (KIR ligand model), mismatch between the donor KIR and recipient HLA (receptor-ligand model), and expression of specific donor KIR haplotypes enriched for activating KIR (KIR haplotype model). When alloreactivity is predicted in the graft-versus-host direction, donor NK cells become activated and carry out cytotoxic effector functions against the recipient’s tumor cells. Created with (Biorender.com).
Figure 3
Figure 3
Dynamic Changes in Glucose Metabolism Underly NK Cell Effector Potential. NK cells are primarily fueled by glucose. Following uptake into the cytoplasm, glucose is first converted to pyruvate through glycolysis, generating two molecules of adenosine triphosphate (ATP) per glucose molecule. Pyruvate is then either converted to lactate and expelled from the cell or transported to the mitochondria where it is further metabolized through the citrate malate shuttle (CMS) to fuel the electron transport chain (ETC) and oxidative phosphorylation (OxPhos), driving efficient production of ATP. Basal rates of glycolysis and OxPhos are sufficient to fuel the homeostatic needs and acute effector functions of resting NK cells. Following prolonged cytokine stimulation NK cells experience an increase in the rates of glycolysis and OxPhos to support their increased capacity for IFNγ production and cytotoxic activity. Highly cytotoxic NK cells can also undergo cytokine-induced metabolic reprogramming towards glycolysis through the mechanistic target of rapamycin (mTOR), a master regulator of cellular metabolism. An increased capacity for glucose-driven metabolism and more robust activation of the mTOR pathway identifies NK cells with the greatest cytotoxic potential. Created with (Biorender.com).
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