Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity

oleh: Baige Yao, Baige Yao, Qinglan Yang, Qinglan Yang, Yao Yang, Yana Li, Yana Li, Hongyan Peng, Hongyan Peng, Shuting Wu, Shuting Wu, Lili Wang, Lili Wang, Shuju Zhang, Shuju Zhang, Minghui Huang, Minghui Huang, Erqiang Wang, Erqiang Wang, Peiwen Xiong, Peiwen Xiong, Ting Luo, Ting Luo, Liping Li, Liping Li, Sujie Jia, Yafei Deng, Yafei Deng, Youcai Deng

Format: Article
Diterbitkan: Frontiers Media S.A. 2021-12-01

Deskripsi

Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.