Natural killer (NK) cells are key players in the immune system. They use receptors on their cell surface to identify target cells. However, to escape being killed by the immune system, cancer cells such as thyroid cancer cells, use various methods to suppress the function of NK cells. Thus, this study aims to elucidate how thyroid cancer cells downregulate NK cell function in a co-culture system. We found that thyroid cancer cells suppress NK cell cytotoxicity and inhibit the expression of activating receptors, such as NKG2D and NKp46, by regulating indoleamine 2,3-dioxygenase (IDO). Also, thyroid cancer cells produce kynurenine using IDO, which causes NK cell dysfunction. Kynurenine enters NK cells via the aryl hydrocarbon receptor (AhR) on the surfaces of the NK cells, which decreases NK cell function and NK receptor expression via the signal transducer and activator of transcription (STAT) 1 and STAT3 pathways. In addition, STAT1 and STAT3 directly regulated the expression of NKG2D and NKp46 receptors by binding to the promoter region. Conclusively, NK cell function may be impaired in thyroid cancer patients by IDO-induced kynurenine production. This implies that IDO can be used as a target for thyroid cancer therapeutics aiming at improving NK cell function.

Ginseng is one of the most widely used herbal remedies for various diseases worldwide. Ginsenoside Rg3 (G-Rg3), the main component of ginseng, possesses several pharmacological properties, including anti-inflammatory, anti-tumor, antioxidant, anti-obesity, and immunomodulatory activities. However, the effect of G-Rg3 on natural killer (NK) cells in humans is not fully understood. Here, we investigated the effect of G-Rg3 on NK cell function and differentiation and elucidated the underlying mechanism. G-Rg3 increased NK cell cytotoxicity and simultaneously increased the expression of NK-activating receptors, NKp44, NKp46, and NKp30. Additionally, G-Rg3 increased the mRNA expression of NK cytolytic molecules, granzyme B and perforin. The expression of CD107a, a marker of NK cell degranulation, also increased in G-Rg3-treated NK cells. We therefore proceeded to identify which MAPK signaling pathway was involved in G-Rg3-mediated cytolytic activity. Treatment with G-Rg3 increased the phosphorylation levels of extracellular signal-regulated kinase (ERK), whereas ERK inhibition eliminated G-Rg3-induced NK cell cytotoxicity, suggesting the involvement of the ERK pathway. G-Rg3 did not affect the rate of differentiation of human cord-blood-derived NK cells; however, it increased the functional maturation of differentiated NK cells and promoted their cytotoxicity. The G-Rg3 isomer, 20(R)-Rg3, effectively activated NK cells via the extracellular signal-regulated kinase (ERK) signaling pathway, whereas 20(S)-Rg3 had no effect on NK cell activity. Altogether, the results demonstrated that 20(R)-Rg3 promoted NK cell activity via activation of the MAPK/ERK pathway, suggesting that 20(R)-Rg3 may be used as an activator of NK cell cytotoxicity for the treatment of diverse types of cancers.

Kang YJ, et al. Immune Netw. 2023 Jan;23(2):e14. https://doi.org/10.4110/in.2023.23.e14

Helixor A, an anticancer drug, has an immunostimulatory effect that increases T and natural killer (NK) cell activity in patients with cancer and endometriosis. However, the molecular mechanisms underlying its effect on NK cells in these patients are not fully understood. In this study, we investigated the effect of helixor A on the activation and differentiation of NK cells, and elucidated the underlying mechanisms. Helixor A enhanced the cytotoxic activity of NK cells in a dose-dependent manner and simultaneously increased the expression of NK-activating receptors, particularly NKp44 and NKp30. It also increased the expression of cytolytic granules, such as granzyme B and perforin, as well as the expression of CD107a, a marker of NK cell degranulation. In addition, the production of IFN-γ and TNF-α was increased in NK cells. However, helixor A did not significantly affect the differentiation of NK cells from CD34⁺ hematopoietic cells. Mechanistically, helixor A activated the p38/MAPK pathway and upregulates PAI-1 expression. Inhibition of the p38 pathway abolished helixor A-induced upregulation of cytotoxic activity and PAI-1 expression in NK cells. In addition, PAI-1 overexpression in NK cells increased cytotoxicity against target cells and p38 phosphorylation. Furthermore, a PAI-1 promoter assay showed that p38 increased PAI-1 transcriptional activity. It was also confirmed that p38 interacts with PAI-1, and this interaction is increased by helixor A treatment in NK cells. Collectively, helixor A may serve as a therapeutic agent to increase NK cell cytotoxicity or transduction of PAI-1 in NK cells can be transplanted as a gene therapy.