ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.
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Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 12 citations in OpenAlex.
- Decoding the crosstalk between ubiquitination and other post-translational modifications in cancer immunity: from mechanisms to clinical prospects.NPJ precision oncology · 2026Review
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- Post-Translational Modifications: Key "Regulators" of Pancreatic Cancer Malignant Phenotype-Advances in Mechanisms and Targeted Therapies.Biomedicines · 2025Review
- Vitamin B12 in Cancer Patients: Clinical Insights into Deficiency, Excess, Diagnosis, and Management.Nutrients · 2025Review
- Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.Molecular cancer · 2025Review
- Programmed Cell Death Ligand as a Biomarker for Response to Immunotherapy: Contribution of Mass Spectrometry-Based Analysis.Cancers · 2025Review
- Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression.Genes & diseases · 2025Review
- Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.The Journal of clinical investigation · 2025Article
- Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways.Experimental hematology & oncology · 2024Review
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22 authors at 2 institutions in 1 country.
Kang SunDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Xiaozhen ZhangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Mengyi LaoDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Lihong HeDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Sicheng WangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Hanshen YangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jian XuDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jianghui TangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Zhengtao HongDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jinyuan SongDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Chengxiang GuoDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Muchun LiDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Xinyuan LiuDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Yan ChenDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Hanjia ZhangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jingxing ZhouDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jieru LinDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Sirui ZhangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Yifan HongDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Jinyan HuangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China.
Tingbo LiangDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China. Electronic address: liangtingbo@zju.edu.cn.
Xueli BaiDepartment of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Innovation Center for the Study of Pancreatic Diseases, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Zhejiang University, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China. Electronic address: shirleybai@zju.edu.cn.
Zhejiang University · CNZhejiang Cancer Hospital · CN
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.
Indexed as
B7-H1 AntigenCarcinoma, Pancreatic DuctalCD8-Positive T-LymphocytesLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Pancreatic NeoplasmsAnimalsCell Line, TumorDisease Models, AnimalGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsImmunotherapyMicePhosphorylationB7-H1 AntigenCD274 protein, humanImmune Checkpoint InhibitorsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, humanimmunotherapy inhibitorLRRK2PDACPD-L1
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