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A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis.
Molecular immunology Pub Date : 2020-05-06 , DOI: 10.1016/j.molimm.2020.04.016
Chengui Lu 1 , Changjiang Guo 2 , Han Chen 2 , Huiyong Zhang 2 , Lingtong Zhi 2 , Tanyu Lv 2 , Mingfeng Li 2 , Zhiyuan Niu 2 , Ping Lu 3 , Wuling Zhu 2
Affiliation  

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.

中文翻译:


一种新型嵌合 PD1-NKG2D-41BB 受体通过触发焦亡增强 NK92 细胞对人肺癌 H1299 细胞的抗肿瘤活性。



嵌合抗原受体(CAR)修饰的过继自然杀伤(NK)细胞代表了一种有前途的癌症治疗免疫治疗方式,但在实体瘤中面临许多挑战。一个主要障碍是包括 PD1 在内的抑制性受体 (IR) 诱导的免疫抑制作用。为了干扰PD1信号传导以增强CAR-NK细胞对抗实体瘤的活性,我们合理设计了一种新型嵌合共刺激转换受体(CCCR),主要包含PD1的胞外结构域、NKG2D的跨膜和胞质结构域以及NKG2D的胞质结构域。 41BB。这种 NK 定制的 CCCR 能够将负性 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,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细胞诱导的广泛焦亡引起的。在肺癌异种移植模型中,CCCR-NK92 细胞显着抑制肿瘤生长。我们的结果凸显了使用 NK 定制的 CCCR 工程 NK92 细胞治疗人类肺癌的免疫治疗潜力。
更新日期:2020-05-06
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