Understanding NK cell biology for harnessing NK cell therapies: targeting cancer and beyond

Abstract

Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain hematologic malignancies. However, there are several limitations that need to be addressed to target more cancer types. Natural killer (NK) cells are a type of innate immune cells that represent a unique biology in cancer immune surveillance. In particular, NK cells obtained from heathy donors can serve as a source for genetically engineered immune cell therapies. Therefore, NK-based therapies, including NK cells, CAR-NK cells, and antibodies that induce antibody-dependent cellular cytotoxicity of NK cells, have emerged. With recent advances in genetic engineering and cell biology techniques, NK cell-based therapies have become promising approaches for a wide range of cancers, viral infections, and senescence. This review provides a brief overview of NK cell characteristics and summarizes diseases that could benefit from NK-based therapies. In addition, we discuss recent preclinical and clinical investigations on the use of adoptive NK cell transfer and agents that can modulate NK cell activity.

Keywords: aging; cancer; chimeric antigen receptor; immune surveillance; immunotherapy; natural killer cell.

Figure 1

Developmental process of NK cells. NK cells originates from HSCs and CLPs in the bone marrow. The immature NK cells express CD122 and NCRs, such as NKp46, NKp30, and NKp44. Chemokine receptors, including CXCR3, CX3CR1, and S1P5R, are involved in the egression of NK cells. In the blood, two types of NK cells are majorly found, CD56^bright and CD56^dim, with CD56^dim NK cells expressing CD16. Long-lived NK cells can be distinguished by increased expression of CD57. Tissue-resident NK cells express CD49a, CD103, CD69, and CD56. The blocked arrows with dotted lines suggest that further research is required to fully understand these processes. HSC, hematopoietic stem cell; LMPP, lympho-myeloid primed progenitor; CLP, common lymphoid progenitor; NKP, NK progenitor; iNK, immature NK; mNK, mature NK; NCR, NK cell receptor; KIR, killer cell immunoglobulin-like receptor; VLA-4, very late antigen-4.

Figure 2

A schematic overview of signal transduction pathway for NK cell activation. Upon recognition of ligands, activation receptors on NK cell surface initiate intracellular signaling via adaptor proteins DAP10 and DAP12. These signaling pathways stimulate the transcription of genes involved in cytokines and cytotoxicity, which are key functions of NK cell surveillance. DAP12, DNAX-activating protein of 12 kDa; DAP10, DNAX-activating protein 10; SAP, slam-associated protein; PI3K, phosphoinositide 3-kinase; Grb2, growth factor receptor-bound protein 2; PAK, p21-activated kinase; JNK, c-Jun N-terminal kinase; SLP-76, Src homology 2 domain-containing leukocyte protein of 76 kDa; PIP₂ , phosphatidylinositol 4,5-bisphosphate; PIP₃ , phosphatidylinositol 3,4,5-triphosphate; PLCγ, phospholipase C γ; IP₃ , inositol 1,4,5-triphosphate; CaM, calmodulin; CaN, calcineurin; NFAT, nuclear factor of activated T-cells; DAG, diacylglycerol; PKC, protein kinase C; MSK1, mitogen and stress activated protein kinase-1; IKK, IκB kinase; IκB, inhibitor of NFκB; NFκB, nuclear factor kappa B; PDK, phosphoinositide dependent kinase; Akt, protein kinase B; TSC, tuberous sclerosis complex; RHEB, ras homologue enriched in brain; mTORC1, mammalian target of rapamycin complex 1; 4E-BP1, eIF4E-binding protein 1; eIF-4E, eukaryotic initiation factor 4E; S6K1, ribosomal protein S6 kinase beta-1.

Figure 3

An overview of current and emerging approaches for harnessing NK cell activity. Adoptive transfer of NK cells has demonstrated efficacy in treating tumors, and various strategies have been employed to further improve their function. These include introducing CARs, chemokine receptors, and other modifications via genome editing using CRISPR-Cas system. Additionally, ADCC has been shown to efficiently induce NK cell killing activity. Clinical trials are underway for various therapies for inducing ADCC, including mAbs, BiKEs, and TriKEs. Researches on developing TME inhibitors and cytokines to enhance cell activity, and combinations of these agents with NK cells or other treatments are also being explored. NK cell therapy is also being investigated for novel indications such as viral infections and aging, using therapeutic NK cells to eliminate damaged cells. CAR, chimeric antigen receptor; mAb, monoclonal antibody; BiKE, bi-specific killer engager; TriKE, tri-specific killer engager; sMIC, soluble MHC I chain-related molecules A and B; DPP4, dipeptidyl peptidase-4; IDO, indoleamine-pyrrole 2,3-dioxygenase; TME, tumor microenvironment; DNRII, dominant-negative TGF-β receptor 2.