CRISPR篩選鑒定出新的免疫治療靶標



本期文章:《細胞》:Volume 178 Issue 5

耶魯大學醫學院Sidi Chen研究團隊在CD8 T細胞中,利用基因組規模的體內CRISPR篩選鑒定出新的免疫治療靶標。這一研究成果發表在2019年8月22日出版的《細胞》上。

研究人員在癌癥免疫治療環境下直接在CD8 T細胞中進行基因組規模的CRISPR篩選,并鑒定了腫瘤浸潤和肥大細胞脫顆粒的調節者。體內篩選強有力地重新鑒定了典型的免疫治療靶標,例如PD-1和Tim-3,以及尚未在T細胞中表征的基因。侵入和脫粒篩選均鑒定到RNA解旋酶Dhx37。Dhx37敲除增強了抗體特異性CD8T細胞對體內三陰性乳腺癌的功效。小鼠和人CD8 T細胞中的免疫學表征揭示DHX37參與抑制效應功能、細胞因子產生和T細胞活化。轉錄組學分析和生物化學測試揭示了DHX37在調節NF-κB中的作用。這些數據表明高通量體內遺傳篩選可用于免疫療法靶標發現,并建立了DHX37作為CD8T細胞的功能調節者。

研究人員表示,CD8 T細胞在抗腫瘤免疫反應中起重要作用。

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:

期刊信息

Cell:《細胞》,創刊于1974年。隸屬于細胞出版社,最新IF:36.216

官方網址:https://www.cell.com/

投稿鏈接:https://www.editorialmanager.com/cell/default.aspx




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