Clinical Applications of Natural Killer Cells

Abstract

Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody-dependent cellular cytotoxicity, the manipulation of receptor-mediated activation, inclusion criteria based on killer cell immunoglobulin-like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)-engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK-mediated antitumor effects may be achieved without the risk of graft-versus-host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years.

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

“…Also, NK cell development requires the presence of the family of 6 γ chain containing receptors: IL-2R, IL-4R, IL-7R, Il-9R, IL-15R, and IL-21R [7]. Activation of NK cells is regulated by several receptors including: (1) KIRs, (2) CD94-NKG2 family, (3) leukocyte immunoglobulin-like receptors, (4) natural cytotoxicity receptors, and (5) FcγRIIIa (CD16) [12]. After activation, NK cells have the following 3 main functions to participate in immune defense: (1) ability to mediate contactdependent killing of target cells through mobilization of highly specialized organelles or lytic granules in NK cells; (2) production of soluble factors such as cytokines, chemokines and other regulators to promote direct antidisease effects and to further induce and regulate immunity; and (3) promotion and regulation of immunity through contact-dependent costimulatory and regulatory mechanisms [31].…”

“…The molecular mechanisms that regulate NK cell cytotoxicity can be divided into 3 main processes: target cell recognition, target cell contact and immunological synapse, and NK cell-induced target cell death [7]. NK cells contain cytoplasmic granules that include perforin which is a membrane-disrupting protein and granzyme family of serine proteases and they express death ligands which are members of the tumor necrosis factor (TNF) superfamily including: (1) TNF-related apoptosis-inducing ligand, (2) Fas ligand (FasL) which is expressed on activated NK cells and cytotoxic T lymphocytes, and (3) TNF-like weak inducer of apoptosis [12]. The following factors may potentially in luence immune response: expression genes, genetic mutations, alteration of resistance to immunotherapies in leukemic cells, tumor microenvironment consisting of T regulatory cells (T-regs), tumor-associated macrophages, myeloid-derived suppressor cells, and production of cytokines [32].…”

“…NK cells selectively kill target cells that downregulate MHC molecules and/or upregulate other activating ligands such as MHC class I chain (MIC)-related antigens: MICA, MICB, and UL-16 binding protein. The use of perforin and granzyme in cytolytic killing is a major mechanism in the elimination of infected cells and tumor cells by NK cells [12].…”

“…Preparation of NK cells for clinical use is a complicated process that involves multiple steps and depends on the following factors: (1) the desired primary source of NK cells such as PB, BM, UCB, hESCs, and iPSCs; (2) the speci ic cell line to be used; and (3) whether to use autologous or allogeneic NK cells. However, details of the steps involved in preparation, manufacture, delivery and tracing of NK cells are shown in table 5 [12,[158][159][160][161][162]. The types of available NK cell-based immunotherapies are shown in table 6 [12].…”

“…They develop from common progenitors and differentiate from hematopoietic stem cells (HSCs) in the bone marrow (BM) but diverge into distinct subsets which differ in cytokine production, cytotoxicity, homing and memory traits [10,11]. NK cells can be derived from: BM, PB, cryopreserved umbilical cord blood (UCB), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and various cell lines such as NK-92 and KHYG-1 [1,12,13].…”