Natural Killer Cells: A Review of Biology, Therapeutic Potential and Challenges in Treatment of Solid Tumors

Abstract

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells’ biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.

Phenotypic and Functional Changes in Peripheral Blood Natural Killer Cells in Crohn Disease Patients

“…We determined the expression of different non-KIR receptors on NK cells in the peripheral blood of CD patients and healthy control subjects. The expression of CD69 (an early marker of lymphocyte activation) [31], NKG2C (an activating receptor of the NKG2 family that binds to HLA-E [3]), NKG2D (an atypical member of the NKG2 family that binds to stress-induced proteins [3,32]), and IL-23R (a component of the receptor complex that binds to IL-23 and whose genetic mutations have been associated with CD [33]) as well as the percentages of NK cells expressing these receptors was increased significantly (p < 0:05) in CD patients as compared with healthy control subjects ( Figure 4). In contrast, although the expression of NKG2A (an inhibitory receptor of the NKG2 family that binds to HLA-E [3]) showed nonsignificant (p > 0:05) changes, the percentages of NK cells expressing this inhibitory receptor decreased significantly (p < 0:05) in the patients.…”

“…CXC3R1 is a C-X3-C-type chemokine receptor that binds to CXC3L1/fractalkine and is implicated in the chemotaxis of immune cells to sites of inflammation in the body [36]. NKp46 and NKp44 are activating receptors belonging to the Natural Cytotoxicity Receptor (NCR) family [3]. The expression levels of CX3CR1 on NK cells tended to increase in CD patients compared with healthy controls; however, the increase was not significant (p = 0:128).…”

“…Natural Killer (NK) cells are important effector cells of the innate immune system. They comprise about 10-15% of the mononuclear cells in the peripheral blood [1][2][3]. Phenotypically, they are non-T and non-B lymphocytes and express CD16 (FcγRIIIa; the low-affinity receptor for the Fc region of IgG) and CD56 (an isoform of the Neural Cell Adhesion Molecule (N-CAM)) on their surface.…”

“…NK cells can target and kill autologous cells of the body when the latter become infected with intracellular pathogens (e.g., viruses) and are transformed or stressed due to DNA damage and/or inflammatory stimuli. They can also kill and eliminate target cells with the help of antibodies in a process called antibody-dependent cell-mediated cytotoxicity (ADCC) [3,5]. The cells targeted in ADCC express specific antigens for the antibodies, which bind to CD16 on NK cells.…”

“…NK cells express a wide variety of inhibitory and activating receptors as well as costimulatory molecules on their surface [3,11,12]. The receptors and coreceptors bind to their cognate ligands on the surface of target cells.…”