CRISPR-Cas9筛选发现了一个IRF1-SOCS1介导的负反馈回路，限制CXCL9表达和抗肿瘤免疫。
CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity.
发表日期：2023 Aug 20
作者：
Imran G House, Emily B Derrick, Kevin Sek, Amanda X Y Chen, Jasmine Li, Junyun Lai, Kirsten L Todd, Isabelle Munoz, Jessica Michie, Cheok Weng Chan, Yu-Kuan Huang, Jack D Chan, Emma V Petley, Junming Tong, DatMinh Nguyen, Sven Engel, Peter Savas, Simon J Hogg, Stephin J Vervoort, Conor J Kearney, Marian L Burr, Enid Y N Lam, Omer Gilan, Sammy Bedoui, Ricky W Johnstone, Mark A Dawson, Sherene Loi, Phillip K Darcy, Paul A Beavis
来源：
Cell Reports
摘要：
CXCL9表达是免疫检查点阻断治疗反应的强力预测因子。因此，我们试图开发增强CXCL9表达和增强抗肿瘤免疫的治疗策略。为了进行CXCL9表达调控因子的全基因组CRISPR-Cas9筛选，采用CRISPR knockin策略生成了CXCL9-GFP报告基因株系。该方法发现，IRF1通过诱导SOCS1来限制肿瘤细胞和原始髓细胞中的CXCL9表达，进而限制STAT1信号传导。因此，我们鉴定了一组STAT1依赖基因的亚组，这些基因的转录不需要IRF1，包括CXCL9。靶向IRF1或SOCS1都能有效增强肿瘤内巨噬细胞的CXCL9表达，在免疫检查点阻断治疗背景下进一步增强。因此，我们揭示了IRF1通过诱导SOCS1来限制一部分STAT1依赖基因表达的非经典作用。版权所有©2023作者。由Elsevier Inc出版。保留所有权利。
CXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought to develop therapeutic strategies to enhance the expression of CXCL9 and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators of CXCL9 expression, a CXCL9-GFP reporter line is generated using a CRISPR knockin strategy. This approach finds that IRF1 limits CXCL9 expression in both tumor cells and primary myeloid cells through induction of SOCS1, which subsequently limits STAT1 signaling. Thus, we identify a subset of STAT1-dependent genes that do not require IRF1 for their transcription, including CXCL9. Targeting of either IRF1 or SOCS1 potently enhances CXCL9 expression by intratumoral macrophages, which is further enhanced in the context of immune checkpoint blockade therapy. We hence show a non-canonical role for IRF1 in limiting the expression of a subset of STAT1-dependent genes through induction of SOCS1.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.