Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/33623
Title: CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity.
Austin Authors: House, Imran G;Derrick, Emily B;Sek, Kevin;Chen, Amanda X Y;Li, Jasmine;Lai, Junyun;Todd, Kirsten L;Munoz, Isabelle;Michie, Jessica;Chan, Cheok Weng;Huang, Yu-Kuan;Chan, Jack D;Petley, Emma V;Tong, Junming;Nguyen, DatMinh;Engel, Sven;Savas, Peter;Hogg, Simon J;Vervoort, Stephin J;Kearney, Conor J;Burr, Marian L;Lam, Enid Y N;Gilan, Omer;Bedoui, Sammy;Johnstone, Ricky W;Dawson, Mark A;Loi, Sherene;Darcy, Phillip K;Beavis, Paul A
Affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
Department of Microbiology and Immunology at the Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia; Institute of Experimental Immunology, University of Bonn, Bonn, Germany.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia.
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia.
Issue Date: 20-Aug-2023
Date: 2023
Publication information: Cell Reports 2023-08-20; 42(8)
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/33623
DOI: 10.1016/j.celrep.2023.113014
ORCID: 
Journal: Cell Reports
Start page: 113014
PubMed URL: 37605534
ISSN: 2211-1247
Type: Journal Article
Subjects: CP: Cancer
CRISPR-Cas9
Cxcl10
Cxcl9
DCs
Irf1
Socs1
cancer
immunotherapy
macrophages
Appears in Collections:Journal articles

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