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

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• CXCL9 expression predicts response to immune checkpoint blockade (ICB) therapy.
• Enhancing CXCL9 expression is a therapeutic goal to augment antitumor immunity.

Purpose of the Study:

• To identify regulators of CXCL9 expression using CRISPR-Cas9 screening.
• To develop strategies for enhancing CXCL9 expression and antitumor immunity.

Main Methods:

• Generated a CXCL9-GFP reporter line via CRISPR knockin.
• Performed whole-genome CRISPR-Cas9 screening to identify CXCL9 regulators.
• Investigated the role of IRF1, SOCS1, and STAT1 signaling in CXCL9 regulation.

Main Results:

• Identified IRF1 as a limiter of CXCL9 expression in tumor and myeloid cells via SOCS1 induction.
• Discovered a subset of STAT1-dependent genes, including CXCL9, that do not require IRF1 for transcription.
• Demonstrated that targeting IRF1 or SOCS1 significantly enhances CXCL9 expression in macrophages, further boosted by ICB therapy.

Conclusions:

• IRF1 plays a non-canonical role in limiting STAT1-dependent gene expression through SOCS1 induction.
• Targeting IRF1 or SOCS1 represents a promising strategy to enhance CXCL9-mediated antitumor immunity, particularly in combination with ICB therapy.