Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities

Abstract

Cancer immunotherapy has been firmly established as a new milestone for cancer therapy, with the development of multiple immune cells as therapeutic tools. Natural killer (NK) cells are innate immune cells endowed with potent cytolytic activity against tumors, and meanwhile act as regulatory cells for the immune system. The efficacy of NK cell-mediated immunotherapy can be enhanced by immune stimulants such as cytokines and antibodies, and adoptive transfer of activated NK cells expanded ex vivo. In addition, NK cells can arm themselves with chimeric antigen receptors (CARs), which may greatly enhance their anti-tumor activity. Most recently, extracellular vesicles (EVs) derived from NK cells show promising anti-tumor effects in preclinical studies. Herein, we carefully review the current progress in these NK cell-based immunotherapeutic strategies (NK cells combined with stimulants, adoptive transfer of NK cells, CAR-NK cells, and NK EVs) for the treatment of cancers, and discussed the challenges and opportunities for opening a new horizon for cancer immunotherapy.

Keywords: adoptive cellular immunotherapy; antibodies; cancer immunotherapy; chimeric antigen receptor; cytokines; extracellular vesicles; natural killer cell.

Figure 1

Various NK cell-based immunotherapy approaches. (A) Administration of stimulatory cytokines and antibodies to patients triggers activation and expansion of the autologous NK cells and enhance their cytotoxicity. (i) Cytokine. “Super” agonist of IL-2 improves its affinity for IL-2/15Rβ. Arrow width indicates expected intensity of IL-2 signaling. The “super” agonist of IL-15 mimics the physiological trans-presentation of IL-15 to NK cells without the involvement of antigen-presenting cells. (ii) Antibodies. Binding of CD16 to the Fc portion of TAA mAbs leads to NK cells activation and ADCC. Application of BiKE or TriKE target to CD16 or NKG2D (on NK cells) and tumor antigens promotes the formation of immune synapses between NK cells and tumor cells. mAbs against inhibitory receptors on NK cells facilitate NK cytotoxicity. (B) Adoptive transfer of NK cells. (i) NK cells obtained from PBMCs, NK cell lines or hPSCs can be infused into patients directly or in conjunction with immune stimulants. (ii) NK cells are designed to express chimeric antigen receptors (CAR), which are then allowed to expand ex vivo before being transfused back into the patient. (C) Infusion of engineered NK cells and NK/CAR-NK cell derived EVs. Culture medium of expanded NK cells or CAR NK cells can be exploited to isolate EVs and then infused into the patient. TAA, Tumor-associated antigen; PD-L1, Programmed death ligand-1; ECM, Extracellular matrix.

Figure 2

Characteristics and anti-tumor mechanisms of NK EVs. (A) A typical micrograph of transmission electron showing extracellular vesicles obtained from NK cells; scale bar, 200 nm. (B) Mechanisms by which NK EVs may interact with target cells.