CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma

doi:10.1136/jitc-2023-007529

科研成果详情

题名	CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma
作者	Ruonan Zhang1,2; Jie Wang 1; Yu Du 3; Ze Yu1; Yihan Wang 4; Yixiao Jiang 5; Yixin Wu 1; Ting Le 1; Ziqi Li 1; Guoqiang Zhang 5; Lei Lv 6; Haijie Ma 7
发表日期	2023-11-24
发表期刊	Journal for immunotherapy of cancer 影响因子和分区
语种	英语
原始文献类型	Journal Article ; Article
关键词	Immune Checkpoint Inhibitors Immunotherapy Tumor Biomarkers
其他关键词	CYCLIN-DEPENDENT KINASE-5 ; ANTITUMOR IMMUNITY ; INHIBITION ; EXPRESSION ; STABILIZATION ; BLOCKADE ; TARGETS ; CMTM6
摘要	In the past few years, immunotherapies of hepatocellular carcinoma (HCC) targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved durable clinical benefits. However, only a fraction of HCC patients showed objective clinical response to PD-1/PD-L1 blockade alone. Despite the impact on post-translational modifications of PD-L1 being substantial, its significance in resistance to HCC immunotherapy remains poorly defined., Cyclin-dependent kinase 5 (CDK5) expression was knocked down in HCC cells, CDK5 and PD-L1 protein levels were examined by Western blot. Coimmunoprecipitation was conducted to evaluate the interaction between proteins. Preclinical HCC mice model was constructed to evaluate the effect of CDK5 inhibitor alone or in combination with PD-1 antibody. Clinical HCC samples were used to elucidate the clinical relevance of CDK5, PD-L1, and PD-L1 T290 phosphorylation in HCC., We find that CDK5 deficiency upregulates PD-L1 protein expression in HCC cells and decipher a novel molecular mechanism under which PD-L1 is downregulated by CDK5, that is, CDK5 mediated PD-L1 phosphorylation at T290 promotes its binding with chaperon protein heat-shock cognate protein 70 (HSC70) and degradation through chaperon-mediated autophagy. Notably, treatment of CDK5 inhibitor, PNU112455A, effectively upregulates the tumorous PD-L1 level, promotes the response to anti-PD-1 immunotherapy,and prolongs the survival time of mice bearing HCC tumors. What is more, the T290 phosphorylation status of PD-L1 correlates with the prognosis of HCC., Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.
资助项目	National Natural Science Foundation of China[81502106,81972620,82121004,82172936];Natural Science Foundation of Zhejiang Province[LY15H160047];National Key Research and Development Program of China[2020YFA0803400/2020YFA0803402];
出版者	BMJ PUBLISHING GROUP
ISSN	2051-1426
EISSN	2051-1426
卷号	11 期号:11
DOI	10.1136/jitc-2023-007529
页数	12
WOS类目	Oncology ; Immunology
WOS研究方向	Oncology ; Immunology
WOS记录号	WOS:001124104700001
收录类别	PUBMED ; SCOPUS ; SCIE
URL	查看原文
PubMed ID	38007240
SCOPUSEID	2-s2.0-85177742090
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/185809
专题	其他_附属舟山医院（舟山医院）
作者单位	1.Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China.; 2.MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.; 3.Nourse Centre for Pet Nutrition, Wuhu, Anhui, China.; 4.School of Management, Xi'an Jiaotong University, Xi'an, Shanxi, China.; 5.Department of General Surgery, Zhoushan Hospital, Zhoushan, Zhejiang, China.; 6.MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China haijie215@163.com lvlei@fudan.edu.cn.; 7.Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang, China haijie215@163.com lvlei@fudan.edu.cn.
第一作者单位	其他_附属舟山医院（舟山医院）
第一作者的第一单位	其他_附属舟山医院（舟山医院）
推荐引用方式 GB/T 7714	Ruonan Zhang,Jie Wang,Yu Du,et al. CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma[J]. Journal for immunotherapy of cancer,2023,11(11).
APA	Ruonan Zhang., Jie Wang., Yu Du., Ze Yu., Yihan Wang., ... & Haijie Ma. (2023). CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma. Journal for immunotherapy of cancer, 11(11).
MLA	Ruonan Zhang,et al."CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma".Journal for immunotherapy of cancer 11.11(2023).