耶鲁大学医学院Sidi Chen研究团队在CD8 T细胞中，利用基因组规模的体内CRISPR筛选鉴定出新的免疫治疗靶标。这一研究成果发表在2019年8月22日出版的《细胞》上。

研究人员在癌症免疫治疗环境下直接在CD8 T细胞中进行基因组规模的CRISPR筛选，并鉴定了肿瘤浸润和肥大细胞脱颗粒的调节者。体内筛选强有力地重新鉴定了典型的免疫治疗靶标，例如PD-1和Tim-3，以及尚未在T细胞中表征的基因。侵入和脱粒筛选均鉴定到RNA解旋酶Dhx37。Dhx37敲除增强了抗体特异性CD8T细胞对体内三阴性乳腺癌的功效。小鼠和人CD8 T细胞中的免疫学表征揭示DHX37参与抑制效应功能、细胞因子产生和T细胞活化。转录组学分析和生物化学测试揭示了DHX37在调节NF-κB中的作用。这些数据表明高通量体内遗传筛选可用于免疫疗法靶标发现，并建立了DHX37作为CD8T细胞的功能调节者。

研究人员表示，CD8 T细胞在抗肿瘤免疫反应中起重要作用。

附：英文原文

Title: Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Author: Matthew B. Dong,Guangchuan Wang,Ryan D. Chow,Lupeng Ye,Lvyun Zhu,Xiaoyun Dai,Jonathan J. Park,Hyunu R. Kim,Youssef Errami,Christopher D. Guzman,Xiaoyu Zhou,Krista Y. Chen,Paul A. Renauer,Yaying Du,Johanna Shen,Stanley Z. Lam,Jingjia J. Zhou,Donald R. Lannin,Roy S. Herbst,Sidi Chen

Issue&Volume:  Volume 178 Issue 5

Abstract: CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.

DOI: https://doi.org/10.1016/j.cell.2019.07.044

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30844-X