Zhiheng Zhang , Bojiao Song , Haowei Wei , Yang Liu , Wenjie Zhang , Yuhong Yang , Beicheng Sun
{"title":"NDRG1 通过抑制 ATG9A 依赖性降解 MHC-1 克服了胰腺导管腺癌对免疫疗法的耐药性","authors":"Zhiheng Zhang , Bojiao Song , Haowei Wei , Yang Liu , Wenjie Zhang , Yuhong Yang , Beicheng Sun","doi":"10.1016/j.drup.2023.101040","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><p><span>Pancreatic ductal adenocarcinoma<span> (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the </span></span>treatment of PDAC ICB resistance.</p></div><div><h3>Methods</h3><p><span><span><span>Enrichment of MHC class I<span> was detected by RNA sequence and verified by RT-qPCR and </span></span>immunoblotting in NDRG1-knockdown human </span>pancreatic cancer<span> cell lines. The protein degradation<span> mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and </span></span></span>immunolocalization<span><span>. The roles of NDRG1 and MHC-I in immunotherapy<span> were investigated by orthotopic solid tumors, histology, </span></span>immunohistochemistry<span>, multiplex immunofluorescence staining and flow cytometry.</span></span></p></div><div><h3>Results</h3><p><span>Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of </span>CD8<span> + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. In PDAC patients, NDRG1 expression correlates with high MHC-1 expression and better survival.</span></p></div><div><h3>Conclusion</h3><p><span>Our results reveal NDRG1 in PDAC cancer cells as a </span>tumor suppressor and suggest that pharmaceutically targeting NDRG1 is a promising way to overcome pancreatic cancer resistance to immunotherapy and provides a potential therapeutic strategy for the treatment of pancreatic cancer patients.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-1\",\"authors\":\"Zhiheng Zhang , Bojiao Song , Haowei Wei , Yang Liu , Wenjie Zhang , Yuhong Yang , Beicheng Sun\",\"doi\":\"10.1016/j.drup.2023.101040\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Aims</h3><p><span>Pancreatic ductal adenocarcinoma<span> (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the </span></span>treatment of PDAC ICB resistance.</p></div><div><h3>Methods</h3><p><span><span><span>Enrichment of MHC class I<span> was detected by RNA sequence and verified by RT-qPCR and </span></span>immunoblotting in NDRG1-knockdown human </span>pancreatic cancer<span> cell lines. The protein degradation<span> mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and </span></span></span>immunolocalization<span><span>. The roles of NDRG1 and MHC-I in immunotherapy<span> were investigated by orthotopic solid tumors, histology, </span></span>immunohistochemistry<span>, multiplex immunofluorescence staining and flow cytometry.</span></span></p></div><div><h3>Results</h3><p><span>Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of </span>CD8<span> + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. 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NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-1
Aims
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the treatment of PDAC ICB resistance.
Methods
Enrichment of MHC class I was detected by RNA sequence and verified by RT-qPCR and immunoblotting in NDRG1-knockdown human pancreatic cancer cell lines. The protein degradation mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and immunolocalization. The roles of NDRG1 and MHC-I in immunotherapy were investigated by orthotopic solid tumors, histology, immunohistochemistry, multiplex immunofluorescence staining and flow cytometry.
Results
Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of CD8 + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. In PDAC patients, NDRG1 expression correlates with high MHC-1 expression and better survival.
Conclusion
Our results reveal NDRG1 in PDAC cancer cells as a tumor suppressor and suggest that pharmaceutically targeting NDRG1 is a promising way to overcome pancreatic cancer resistance to immunotherapy and provides a potential therapeutic strategy for the treatment of pancreatic cancer patients.
期刊介绍：
Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation.
Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective.
*Expert reviews in clinical and basic drug resistance research in oncology and infectious disease
*Describes emerging technologies and therapies, particularly those that overcome drug resistance
*Emphasises common themes in microbial and cancer research
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