细胞毒性T细胞
淋巴因子激活杀伤细胞
细胞毒性
癌细胞
癌症研究
自然杀伤细胞
白细胞介素21
生物
NK-92
细胞
癌症
启动(农业)
免疫学
体外
生物化学
发芽
植物
遗传学
作者
Grace Lee,Sheela Karunanithi,Bruce A. Posner,Hanspeter Niederstrasser,Hong Cheng,Yuriy Federov,Shivaprasad Manjappa,Karam Musaitif,Huaiyu Wang,Zachary Jackson,David N. Wald
标识
DOI:10.1007/s00262-021-03117-w
摘要
Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties make NK cells a promising therapeutic against cancer. Limitations of NK cell therapy include deficiencies in high clinical efficacy often due to a need for a high NK cell to target cell ratio to achieve effective killing. In order to address the suboptimal efficacy of current adoptive NK cell therapy, a high throughput screen (HTS) was designed and performed to identify drug-like compounds that increase NK cytotoxic activity against tumor cells without affecting the normal cells. This screen was performed in a 384-well plate format utilizing an expanded primary NK cell product and ovarian cancer cells as a target cell (TC) line. Of the 8000 diverse small molecules screened, 16 hits were identified (0.2% hit rate) based on both a robust Z (RZ) score < -3 and a greater than 10% increase in NK cell killing. A validation screen had a confirmation rate of 70%. Select compounds were further validated and characterized by additional cytotoxicity assays including activity against multiple blood cancer and solid tumor cell lines, with no effect on primary human T cells. This work demonstrates that high-throughput screening can be reliably used to identify compounds that increase NK tumoricidal activity in vitro that can be further investigated and translated for potential clinical application. Précis: Our work led to the identification of promising compound that potently increases NK cell-mediated killing of a variety of different cancer cells, but no impact on the killing of normal cells. This compound demonstrates the utility of this assay.
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