Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma

作者：Xiaotong Lin, Zishen Liu, Xin Dong, Kunyuan Wang, Yao Sun, Han Zhang, Fei Wang, Ying Chen, Ling Jing, Yuetong Guo, Hongjin Xiang, Qiankun Xie, Yuqin Zhang, Zhaoze Guo, Ryohichi Sugimura, Guozhu Xie · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05724-4 · 被引用次数：30 · 研究领域：Immune Cell Function and Interaction、CAR-T cell therapy research、Immune cells in cancer

BACKGROUND: Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. METHODS: Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. RESULTS: In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration ac...