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CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer

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收录情况： ◇ SCIE

作者：
Wang Jian[1,2] * ; Li Run-Ze[3,4] * ; Wang Wen-Jun[5] * ; Pan Hu-Dan[3,4] ; Xie Chun[6] ; Yau Lee-Fong[1] ; Wang Xing-Xia[1] ; Long Wei-Li[7] ; Chen Rui-Hong[1] ; Liang Tu-Liang[3] ; Ma Lin-Rui[1] ; Li Jia-Xin[1] ; Huang Ju-Min[6] ; Wu Qi-Biao[1] ; Liu Liang[3,4] ; He Jian-Xing[5] ; Leung Elaine Lai-Han[6,8] ;
机构： [1]Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China [2]Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China [3]State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China [4]Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China [5]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China [6]Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China. State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau (SAR), China [7]Department of Oncology, Luzhou People’s Hospital, Luzhou, Sichuan, China [8]Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China, Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China
出处：
DOI： 10.1016/j.phrs.2023.106850
ISSN：

关键词： Sphingolipid metabolism CERS4 NSCLC ICIs Rhob CD8+ Tim-3+ T cell

摘要：
Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

基金：
This work was funded by Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery (Grant no. 001/2020/ALC), regular grants (Project no: 0003/2019/AKP, 0096/2018/A3, 0111/2020/A3, 0056/ 2020/AMJ & 0063/2022/A2) from Macao Science and Technology Development Fund, the National Natural Science Foundation of China (82204677), the NSFC overseas and Hong Kong and Macao Scholars Cooperative Research Fund Project (Project no: 81828013), the Science and Technology Projects in Guangzhou (SL2022A04J00459), the Technology Research Projects of State Key Laboratory of Dampness Syndrome of Chinese Medicine (no. SZ2022KF20), the Guangdong Basic and Applied Basic Research Foundation (2020B1515130005) and the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine) (No: 2020B1212030006). This work was also supported by 2020 Young Qihuang Scholar funded by National Administration of Traditional Chinese Medicine and also financially supported by the Start-up Research Grant of University of Macau (SRG2022-00020- FHS) and the Faculty of Health Sciences, University of Macau. This work is also financially supported by the FDCT Funding Scheme for Postdoctoral Researchers of Higher Education Institutions (0017/2021/ APD), the 2023 State Key Laboratory of Quality Research in Chinese Medicine (UM) Internal Research Grant (IRG) (SKL-QRCM-IRG2023- 001), and the FSCPO project (type 1) from Faculty of Health Sciences, University of Macau.
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外文
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中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 1 区 药学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药学
JCR分区：
出版当年[2023]版：
Q1 PHARMACOLOGY & PHARMACY
最新[2023]版：
Q1 PHARMACOLOGY & PHARMACY

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery/State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China [2]Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
共同第一作者：
通讯作者：
通讯机构： [3]State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China [4]Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China [6]Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), China. State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau (SAR), China [8]Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China, Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China
推荐引用方式(GB/T 7714)：
Wang Jian,Li Run-Ze,Wang Wen-Jun,et al.CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer[J].PHARMACOLOGICAL RESEARCH.2023,194:doi:10.1016/j.phrs.2023.106850.
APA：
Wang Jian,Li Run-Ze,Wang Wen-Jun,Pan Hu-Dan,Xie Chun...&Leung Elaine Lai-Han.(2023).CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer.PHARMACOLOGICAL RESEARCH,194,
MLA：
Wang Jian,et al."CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer".PHARMACOLOGICAL RESEARCH 194.(2023)

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