Cell Reports (Aug 2023)
CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity
- 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
Affiliations
- Imran G. House
- 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; Corresponding author
- Emily B. Derrick
- 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
- Kevin Sek
- 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
- Amanda X.Y. Chen
- 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
- Jasmine Li
- 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
- Junyun Lai
- 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
- Kirsten L. Todd
- 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
- Isabelle Munoz
- 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
- Jessica Michie
- 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
- Cheok Weng Chan
- 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
- Yu-Kuan Huang
- 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
- Jack D. Chan
- 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
- Emma V. Petley
- 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
- Junming Tong
- 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
- DatMinh Nguyen
- 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
- Sven Engel
- 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
- Peter Savas
- 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
- Simon J. Hogg
- 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
- Stephin J. Vervoort
- 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
- Conor J. Kearney
- 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; Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia; Department of Anatomical Pathology, The Royal Melbourne Hospital, Melbourne, VIC 3050, Australia; Department of Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; Centre for Cancer Research, The University of Melbourne, Melbourne, VIC 3000, Australia; Department of Immunology, Monash University, Clayton, VIC, Australia
- Marian L. Burr
- 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; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia; Department of Anatomical Pathology, The Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
- Enid Y.N. Lam
- 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
- Omer Gilan
- 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
- Sammy Bedoui
- 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
- Ricky W. Johnstone
- 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
- Mark A. Dawson
- 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; Department of Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia; Centre for Cancer Research, The University of Melbourne, Melbourne, VIC 3000, Australia
- Sherene Loi
- 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
- Phillip K. Darcy
- 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 Immunology, Monash University, Clayton, VIC, Australia; Corresponding author
- Paul A. Beavis
- 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; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 8
p. 113014
Abstract
Summary: 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.
