Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy

Abstract

Natural killer (NK) cells are potent innate immune system effector lymphocytes armed with multiple mechanisms for killing cancer cells. Given the dynamic roles of NK cells in tumor surveillance, they are fast becoming a next-generation tool for adoptive immunotherapy. Many strategies are being employed to increase their number and improve their ability to overcome cancer resistance and the immunosuppressive tumor microenvironment. These include the use of cytokines and synthetic compounds to bolster propagation and killing capacity, targeting immune-function checkpoints, addition of chimeric antigen receptors (CARs) to provide cancer specificity and genetic ablation of inhibitory molecules. The next generation of NK cell products will ideally be readily available as an "off-the-shelf" product and stem cell derived to enable potentially unlimited supply. However, several considerations regarding NK cell source, genetic modification and scale up first need addressing. Understanding NK cell biology and interaction within specific tumor contexts will help identify necessary NK cell modifications and relevant choice of NK cell source. Further enhancement of manufacturing processes will allow for off-the-shelf NK cell immunotherapies to become key components of multifaceted therapeutic strategies for cancer.

Keywords: allogeneic immunotherapy; cancer; natural killer (NK) cells; pluripotent stem cells.

Figure 1

The major activating, co-activating and inhibitory receptors expressed on the surface of NK cells. Abbreviations: 2B4, also known as CD244; CD, cluster of differentiation; DNAM-1, DNAX accessory molecule-1; KIR, killer cell immunoglobulin-like receptors; NKG2, also known as CD159; NKp30, 44, 46, 80, natural cytotoxicity receptors.

Figure 2

Checkpoint inhibitor targets in NK cells and T cells and their respective blocking antibodies under investigation for therapeutic efficacy and/or clinical use for cancer. Blocking antibodies act on their respective targets on NK cells and T cells to potentiate tumor cell killing. Abbreviations: CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HLA-E, human leukocyte antigen-E; KIR, killer cell immunoglobulin-like receptors; MHC, major histocompatibility complex; NK, natural killer; NKG2A, CD94/NK group 2 member A; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TIGIT, T cell immunoreceptor with Ig and ITIM domain; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3.

Figure 3

Effects of NAM, GSK-3 inhibition and HSPs on NK cell function. NAM induces the proliferation and homing of NK cells, while GSK-3 inhibition reduces checkpoint inhibitor transcription. HSPs are endogenous stress signals that induce an upregulation of NKG2C and both GSK-3 inhibition and HSPs induce a rise in TNF-α and IFN-γ levels. Abbreviations: CD, cluster of differentiation; HSP, heat shock protein; IFN-γ, interferon-γ; LAG-3, lymphocyte-activation gene 3; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; PD-1, programmed cell death protein 1; TNF-α, tumor necrosis factor α.

Figure 4

IMiDs mediate indirect augmentation of NK cell function. IMiDs act on IL-2 transcription in T cells to induce the production of TNF-α and IFN-γ and the proliferation of NK cells. Abbreviations: IFN-γ, interferon-γ; IMiD, immunomodulatory imide drugs; IL-2, interleukin-2; TNF-α, tumor necrosis factor-α.

Figure 5

Components of a first-generation CAR. A CAR is made up of the ectodomain (composed of a scFv and hinge), the transmembrane domain and the intracellular signaling endodomain. Abbreviations: scFv; single-chain variable fragment.