2. Academic Validation
  3. DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening

DDR1 is identified as an immunotherapy target for microsatellite stable colon cancer by CRISPR screening

  • NPJ Precis Oncol. 2024 Nov 7;8(1):253. doi: 10.1038/s41698-024-00743-2.
Miaoqing Wu # 1 2,  Wenjuan Ma # 1 2 3,  Guangzhao Lv # 1 2,  Xin Wang 4,  Cong Li 1 2,  Xiang Chen 4,  Xiaofei Peng 4,  Chaoming Tang 4,  Zhizhong Pan 1 2,  Ranyi Liu 5 6,  Gong Chen 7 8,  Rongxin Zhang 9 10
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China.
  • 3 Department of Intensive Care Unit, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China.
  • 4 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, QingYuan, Guangdong, China.
  • 5 Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China. liury@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China. liury@sysucc.org.cn.
  • 7 Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China. chengong@sysucc.org.cn.
  • 8 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China. chengong@sysucc.org.cn.
  • 9 Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, PR China. zhangrx@sysucc.org.cn.
  • 10 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China. zhangrx@sysucc.org.cn.
  • # Contributed equally.
PMID: 39511298 DOI: 10.1038/s41698-024-00743-2
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.

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