Journal article
CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity
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, CJ Kearney Show all
Cell Reports | CELL PRESS | Published : 2023
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..
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Grants
Awarded by Victorian Cancer Agency
Funding Acknowledgements
We acknowledge assistance from the staff of the Animal Facility, the Flow Cytometry Facility, and the Molecular Genomics Core departments at the Peter MacCallum Cancer Center, as well as the Victorian Center of Functional Genomics. The authors also wish to acknowledge the contribution of consumer representatives Karen Gill, Mike Rear, and Graeme Sissing for their contribution to the study. 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.