Lu Chengui, Guo Changjiang, Chen Han, Zhang Huiyong, Zhi Lingtong, Lv Tanyu, Li Mingfeng, Niu Zhiyuan, Lu Ping, Zhu Wuling
Synthetic Biology Engineering Lab of Henan Province, School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China; Sanquan College of Xinxiang Medical University, Xinxiang, Henan Province, PR China.
Synthetic Biology Engineering Lab of Henan Province, School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan Province, PR China.
Mol Immunol. 2020 May 6;122:200-206. doi: 10.1016/j.molimm.2020.04.016.
Chimeric antigen receptor (CAR)-modified adoptive natural killer (NK) cells represent a promising immunotherapeutic modality for cancer treatment but face many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced by inhibitory receptors (IR) including PD1. To interfere with PD1 signaling to augment CAR-NK cells' activity against solid tumors, we rationally designed a novel chimeric costimulatory converting receptor (CCCR), comprising mainly the extracellular domain of PD1, transmembrane and cytoplasmic domains of NKG2D, and the cytoplasmic domain of 41BB. This NK-tailored CCCR was able to switch the negative PD1 signal to an activating signal and hence reversed the immune suppressive effects of PD1. The CCCR-modified NK92 (CCCR-NK92) cells retained typical characteristics of NK cells and exhibited enhanced antitumor activity against human lung cancer H1299 cells in vitro compared with untransduced NK92 cells. The rapid clearance of H1299 cells was caused by CCCR-NK92 cell-induced extensive pyroptosis. In a lung cancer xenograft model, CCCR-NK92 cells significantly inhibited tumor growth. Our results highlight a promising immunotherapeutic potential of using NK-tailored CCCR engineered NK92 cells to treat human lung cancer.
嵌合抗原受体（CAR）修饰的过继性自然杀伤（NK）细胞是一种很有前景的癌症免疫治疗方式，但在实体瘤治疗中面临诸多挑战。一个主要障碍是包括PD1在内的抑制性受体（IR）所诱导的免疫抑制作用。为了干扰PD1信号传导以增强CAR-NK细胞对实体瘤的活性，我们合理设计了一种新型嵌合共刺激转换受体（CCCR），其主要由PD1的胞外结构域、NKG2D的跨膜和胞质结构域以及41BB的胞质结构域组成。这种针对NK细胞定制的CCCR能够将负性的PD1信号转换为激活信号，从而逆转PD1的免疫抑制作用。CCCR修饰的NK92（CCCR-NK92）细胞保留了NK细胞的典型特征，并且与未转导的NK92细胞相比，在体外对人肺癌H1299细胞表现出增强的抗肿瘤活性。H1299细胞的快速清除是由CCCR-NK92细胞诱导的广泛细胞焦亡所致。在肺癌异种移植模型中，CCCR-NK92细胞显著抑制了肿瘤生长。我们的结果凸显了使用针对NK细胞定制的CCCR工程化NK92细胞治疗人类肺癌的潜在免疫治疗前景。
