Title | Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer |
Author | |
Corresponding Author | Liang, Hai-Hai; Fan, Xing-Xing |
Publication Years | 2022-12-08
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DOI | |
Source Title | |
ISSN | 1741-7015
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Volume | 20Issue:1 |
Abstract | BackgroundThe recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR-mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. MethodsGlobal proteomic and phosphoproteomic data from lung cancer tissues were analyzed aiming to map proteins related to non-inflamed TME. The ex vivo and in vivo studies were carried out to evaluate the anti-tumor effect. Proteomics was applied to identify the potential target and signaling pathways. CRISPR-Cas9 was used to knock out target genes. The changes of immune cells were monitored by flow cytometry. The correlation between PKC delta and PD-L1 was verified by clinical samples. ResultsWe proposed that PKC delta, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKC delta enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKC delta significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (alpha PD-1) in vitro and in vivo model. ConclusionsThese findings revealed that PKC delta is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors. |
Keywords | |
URL | [Source Record] |
Indexed By | |
Language | English
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SUSTech Authorship | Others
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Funding Project | Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery["0003/2018/A1","0058/2020/A2"]
; [001/2020/ALC]
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WOS Research Area | General & Internal Medicine
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WOS Subject | Medicine, General & Internal
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WOS Accession No | WOS:000895935400003
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Publisher | |
Data Source | Web of Science
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Citation statistics |
Cited Times [WOS]:2
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Document Type | Journal Article |
Identifier | http://kc.sustech.edu.cn/handle/2SGJ60CL/420787 |
Department | Department of Chemistry |
Affiliation | 1.Macau Univ Sci & Technol, Dr Nehers Biophys Lab Innovat Drug Discovery, State Key Lab Qual Res Chinese Med, Macau, Peoples R China 2.Harvard Med Sch, Dept Cardiol, Boston, MA USA 3.Southern Univ Sci & Technol, Dept Chem, Shenzhen, Guangdong, Peoples R China 4.Sichuan Univ, State Key Lab Biotherapy, Chengdu, Peoples R China 5.Sichuan Univ, West China Hosp, Canc Ctr, West China Med Sch, Chengdu, Peoples R China 6.TianJin Med Univ, Gen Hosp, Tianjin, Peoples R China 7.Harbin Med Univ, Coll Pharm, Dept Pharmacol, Harbin, Heilongjiang, Peoples R China |
Recommended Citation GB/T 7714 |
Zuo, Yi-Han,Gao, Wei-Na,Xie, Ya-Jia,et al. Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer[J]. BMC Medicine,2022,20(1).
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APA |
Zuo, Yi-Han.,Gao, Wei-Na.,Xie, Ya-Jia.,Yang, Sheng-Yong.,Zhou, Jin-Tai.,...&Fan, Xing-Xing.(2022).Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer.BMC Medicine,20(1).
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MLA |
Zuo, Yi-Han,et al."Tumor PKC delta instigates immune exclusion in EGFR-mutated non-small cell lung cancer".BMC Medicine 20.1(2022).
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