美国耶鲁大学陈斯迪等研究人员合作发现，对肿瘤浸润原代自然杀伤（NK）细胞进行体内AAV-SB-CRISPR筛选确定CAR-NK疗法的基因检查点。相关论文于2024年6月25日在线发表在《自然—生物技术》杂志上。

研究人员表示，NK细胞具有抗癌的临床潜力；然而，多种限制因素阻碍了NK细胞疗法的成功。

附：英文原文

Title: In vivo AAV–SB-CRISPR screens of tumor-infiltrating primary NK cells identify genetic checkpoints of CAR-NK therapy

Author: Peng, Lei, Renauer, Paul A., Sferruzza, Giacomo, Yang, Luojia, Zou, Yongji, Fang, Zhenghao, Park, Jonathan J., Chow, Ryan D., Zhang, Yueqi, Lin, Qianqian, Bai, Meizhu, Sanchez, Angelica, Zhang, Yongzhan, Lam, Stanley Z., Ye, Lupeng, Chen, Sidi

Issue&Volume: 2024-06-25

Abstract: Natural killer (NK) cells have clinical potential against cancer; however, multiple limitations hinder the success of NK cell therapy. Here, we performed unbiased functional mapping of tumor-infiltrating NK (TINK) cells using in vivo adeno-associated virus (AAV)–SB (Sleeping Beauty)-CRISPR (clustered regularly interspaced short palindromic repeats) screens in four solid tumor mouse models. In parallel, we characterized single-cell transcriptomic landscapes of TINK cells, which identified previously unexplored subpopulations of NK cells and differentially expressed TINK genes. As a convergent hit, CALHM2-knockout (KO) NK cells showed enhanced cytotoxicity and tumor infiltration in mouse primary NK cells and human chimeric antigen receptor (CAR)-NK cells. CALHM2 mRNA reversed the CALHM2-KO phenotype. CALHM2 KO in human primary NK cells enhanced their cytotoxicity, degranulation and cytokine production. Transcriptomics profiling revealed CALHM2-KO-altered genes and pathways in both baseline and stimulated conditions. In a solid tumor model resistant to unmodified CAR-NK cells, CALHM2-KO CAR-NK cells showed potent in vivo antitumor efficacy. These data identify endogenous genetic checkpoints that naturally limit NK cell function and demonstrate the use of CALHM2 KO for engineering enhanced NK cell-based immunotherapies.

DOI: 10.1038/s41587-024-02282-4

Source: https://www.nature.com/articles/s41587-024-02282-4