异位表达 NKG7 可增强 CAR-T 功能,提高对液体和固体肿瘤的疗效。

IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Yuxin Chen , Meng Wang , Shuxin Huang , Lulu Han , Ying Cai , Xiaodi Xu , Shuwen Sun , Zhaokai Chen , Junze Chen , Jiatian Yu , Hongwei Du , Huizhong Li , Junnian Zheng , Bo Ma , Gang Wang
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引用次数: 0

摘要

由于缺乏治疗后的活检,尤其是实体瘤的活检,限制了人们对体内嵌合抗原受体(CAR)-T细胞相关特征的了解,从而阻碍了提高CAR-T细胞疗效策略的开发。在这里,我们利用消化系统癌症临床样本中的十九个单细胞RNA测序(scRNA-seq)数据,探讨了肿瘤浸润T细胞(TILs)的特征,以确定可能有利于增强CAR-T细胞功能的有效靶点。数据显示,自然杀伤细胞颗粒蛋白7(NKG7)在TILs中过度表达,并与消化道癌症的抗PD1或抗CTLA4治疗呈正相关。随后,我们发现异位表达NKG7能显著提高B7H3靶向CAR-T细胞对B7H3阳性消化道癌细胞(MKN45、Huh7、HuCCT-1、SW620和PANC-1细胞)的细胞毒性,并促进TNF-α和IL-2的表达。此外,在CD19靶向CAR-T模型中,NKG7过表达后的疗效也有所提高。从机理上讲,NKG7能在暴露于相对肿瘤抗原后保持表面CAR表达并促进CAR-T细胞增殖。这些结果表明,利用临床肿瘤样本的单细胞测序数据来寻找提高CAR-T功能的策略是可行的,而异位表达NKG7是提高CAR-T细胞对肿瘤疗效的有效策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ectopic expression of NKG7 enhances CAR-T function and improves the therapeutic efficacy in liquid and solid tumors
Lack of biopsies after treatment, especially in solid tumors, restricts the understanding of chimeric antigen receptor (CAR)-T cells -related characteristic in vivo, thus hindering the development of strategies to improve CAR-T cells efficacy. Here, we applied nineteen individual single-cell RNA sequencing (scRNA-seq) data from clinical samples of digestive cancers to explore the characteristics of tumor-infiltrating T cells (TILs) to identify effective targets which might be benefit for enhancing the function of CAR-T cells. The data showed that natural killer cell granule protein 7 (NKG7) was overexpressed in TILs and positively associated with anti-PD1 or anti-CTLA4 therapy in digestive cancers. Subsequently, we found that ectopic expression of NKG7 significantly improved the cytotoxicity of B7H3-targeting CAR-T cells to B7H3-positive digestive cancer cells (MKN45, Huh7, HuCCT-1, SW620 and PANC-1 cells), as well as promoted the TNF-α and IL-2 expression. Furthermore, in a CD19-targeting CAR-T model, the therapeutic efficacy was also found increased after NKG7 overexpression. Mechanically, NKG7 preserved surface CAR expression and promoted CAR-T cell proliferation after exposing to relative tumor antigen. These results indicated that it may be feasible to explore single-cell sequencing data of clinical tumor samples to find strategies to improve CAR-T function, and that ectopic expression of NKG7 is an effective strategy to improve the therapeutic efficacy of CAR-T cells against tumors.
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来源期刊
Pharmacological research
Pharmacological research 医学-药学
CiteScore
18.70
自引率
3.20%
发文量
491
审稿时长
8 days
期刊介绍: Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.
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