Related Experiment Video
Updated: Jul 29, 2026
Colorectal Cancer Cell Surface Protein Profiling Using an Antibody Microarray and Fluorescence Multiplexing
Published on: September 25, 2011
DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening
Miaoqing Wu1,2, Wenjuan Ma1,2,3, Guangzhao Lv1,2
1Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China.
Abstract:
The role of collagen and its receptor, discoidin domain receptor 1 (DDR1) in immune response of colorectal cancer (CRC) remains unclear. We identified DDR1 as a promising target of immunotherapy resistance using a pooled in vivo CRISPR/sgRNA screening in microsatellite stable (MSS) CRC mouse models. Our findings demonstrated that knockdown or inhibition of DDR1 could enhance infiltration of CD8+ T cells and sensitize MSS CRC to PD-1 blockade. Furthermore, DDR1 was found to facilitate kinase domain phosphorylation, upregulate EZH2, consequently elevating H3K27me3 levels at the CXCL10 promotor, which led to the suppression of CXCL10 transcription once bound to collagen in ECM. Lastly, DDR1 was found positively correlated with collagen I expression in MSS CRC specimens. These findings indicated that targeting DDR1 or its inhibitor 7rh might be potential strategy for overcoming immunotherapy resistance in MSS CRC.
Insights
Targeting discoidin domain receptor 1 (DDR1) can overcome immunotherapy resistance in microsatellite stable colorectal cancer (CRC). Inhibiting DDR1 enhances CD8+ T cell infiltration and sensitizes CRC to PD-1 blockade, offering a new therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The role of collagen and discoidin domain receptor 1 (DDR1) in colorectal cancer (CRC) immune response is not well understood.
- Identifying mechanisms of immunotherapy resistance in microsatellite stable (MSS) CRC is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of DDR1 in immunotherapy resistance in MSS CRC.
- To identify DDR1 as a potential therapeutic target for overcoming resistance to immune checkpoint inhibitors.
Main Methods:
- Pooled in vivo CRISPR/sgRNA screening in MSS CRC mouse models.
- Assessment of CD8+ T cell infiltration and response to PD-1 blockade upon DDR1 knockdown or inhibition.
- Analysis of DDR1-mediated signaling pathways, including EZH2, H3K27me3, and CXCL10 expression.
- Correlation analysis of DDR1 and collagen I expression in MSS CRC patient specimens.
Main Results:
- DDR1 was identified as a key factor in immunotherapy resistance in MSS CRC.
- Knockdown or inhibition of DDR1 enhanced CD8+ T cell infiltration and sensitized MSS CRC to PD-1 blockade.
- DDR1 signaling upregulates EZH2 and H3K27me3, suppressing CXCL10 transcription in the extracellular matrix (ECM).
- DDR1 expression is positively correlated with collagen I in MSS CRC specimens.
Conclusions:
- Targeting DDR1 is a potential strategy to overcome immunotherapy resistance in MSS CRC.
- DDR1 inhibition can enhance anti-tumor immunity by increasing T cell infiltration and restoring CXCL10 expression.
- The DDR1 inhibitor 7rh shows promise for treating MSS CRC patients resistant to immunotherapy.
More Related Videos
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
09:08Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
Published on: June 2, 2021
