CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity

House, IG; Derrick, EB; Sek, K; Chen, AXY; Li, J; Lai, J; Todd, KL; Munoz, I; Michie, J; Chan, CW; Huang, YK; Chan, JD; Petley, EV; Tong, J; Nguyen, D; Engel, S; Savas, P; Hogg, SJ; Vervoort, SJ; Kearney, CJ; Burr, ML; Lam, EYN; Gilan, O; Bedoui, S; Johnstone, RW; Dawson, MA; Loi, S; Darcy, PK; Beavis, PA

Author(s): House, IG; Derrick, EB; Sek, K; Chen, AXY; Li, J; Lai, J; Todd, KL; Munoz, I; Michie, J; Chan, CW; Huang, YK; Chan, JD; Petley, EV; Tong, J; Nguyen, D; Engel, S; Savas, P; Hogg, SJ; Vervoort, SJ; Kearney, CJ; Burr, ML; Lam, EYN; Gilan, O; Bedoui, S; Johnstone, RW; Dawson, MA; Loi, S; Darcy, PK; Beavis, PA;
Details: Publication Year 2023-08-29,Volume 42,Issue #8,Page 113014
Journal Title: Cell Reports
Publication Type: Research article
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.
Publisher: Cell Press
Keywords: CP: Cancer; CRISPR-Cas9; Cxcl10; Cxcl9; DCs; Irf1; Socs1; cancer; immunotherapy; macrophages
Department(s): Laboratory Research; Clinical Haematology; Medical Oncology
PubMed ID: 37605534
Publisher's Version: https://doi.org/10.1016/j.celrep.2023.113014
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2023.113014
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-31 06:07:51

Last Modified: 2023-10-31 06:08:17