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

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posted on 2023-10-26, 04:25 authored by IG House, EB Derrick, K Sek, AXY Chen, J Li, J Lai, KL Todd, I Munoz, J Michie, CW Chan, YK Huang, JD Chan, EV Petley, J Tong, DM Nguyen, S Engel, P Savas, SJ Hogg, SJ Vervoort, Conor KearneyConor Kearney, ML Burr, EYN Lam, O Gilan, S Bedoui, RW Johnstone, MA Dawson, S Loi, PK Darcy, PA Beavis
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.


This work was funded by a National Breast Cancer Foundation Grant (IIRS-19-016) . P.A.B. was supported by a National Breast Cancer Foundation Fellowship (ID# ECF-17-005, 2017-2020) and a Victorian Cancer Agency Mid-Career Fellowship (2021-Current) . I.G.H. was supported by a Victorian Cancer Agency Early Career Fellowship (ECRF20017) . P.K.D. was supported by an NHMRC Senior Research Fellowship (APP1136680) . E.B.D. was supported by scholarships from the Australian Commonwealth Government and Tour de Cure Australia.


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© 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (

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