Cell Reports (Nov 2023)
Targeting VCP potentiates immune checkpoint therapy for colorectal cancer
- Fang Wang,
- Qi Qi,
- Baifu Qin,
- Yiwei Wang,
- Youwei Huang,
- Qing Li,
- Xi Shen,
- Xiangyu Wang,
- Shangqi Yang,
- Guopeng Pan,
- Jiahong Chen,
- Zixi Qin,
- Xueqin Chen,
- Yuqing Yang,
- Yuequan Zeng,
- Jun Liu,
- Yuqin Li,
- Ying Li,
- Zexiong Cheng,
- Xi Lin,
- Fan Xing,
- Yubo Zhang,
- Guocai Wang,
- Kai Li,
- Zhenyou Jiang,
- Haipeng Zhang
Affiliations
- Fang Wang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Qi Qi
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; MOE Key Laboratory of Tumor Molecular Biology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Baifu Qin
- Institute of Molecular and Medical Virology, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Yiwei Wang
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Youwei Huang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong 519000, China; Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, Guangdong 510632, China
- Qing Li
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Xi Shen
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Xiangyu Wang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Shangqi Yang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Guopeng Pan
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Jiahong Chen
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- Zixi Qin
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Xueqin Chen
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Yuqing Yang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Yuequan Zeng
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Jun Liu
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Yuqin Li
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Ying Li
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Zexiong Cheng
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Xi Lin
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Fan Xing
- Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
- Yubo Zhang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
- Guocai Wang
- Institute of Traditional Chinese Medicine & Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
- Kai Li
- Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, China; Corresponding author
- Zhenyou Jiang
- Department of Microbiology and Immunology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China; Corresponding author
- Haipeng Zhang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 11
p. 113318
Abstract
Summary: Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.
