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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
41 Pages Posted: 4 May 2023
More...Abstract
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 CESR4 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.
Funding: 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, 0056/2020/AMJ & 0111/2020/A3) 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), 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 Science, University of Macau.
Declaration of Interest: The authors declare no competing financial interests.
Ethical Approval: All animal experiments were approved by the Use and Care of Animals 202Committee at Macau University of Science and Technology.
Keywords: sphingolipid metabolism, CERS4, NSCLC, ICIs, Rhob, CD8+ Tim-3+ T cell
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