دورية أكاديمية
Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell-Mediated Antitumor Immunity Through PD-L1.
العنوان: | Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell-Mediated Antitumor Immunity Through PD-L1. |
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المؤلفون: | Chui NN; Department of Pathology, The University of Hong Kong, Hong Kong., Cheu JW; Department of Pathology, The University of Hong Kong, Hong Kong., Yuen VW; Department of Pathology, The University of Hong Kong, Hong Kong., Chiu DK; Department of Pathology, The University of Hong Kong, Hong Kong., Goh CC; Department of Pathology, The University of Hong Kong, Hong Kong., Lee D; Department of Pathology, The University of Hong Kong, Hong Kong., Zhang MS; Department of Pathology, The University of Hong Kong, Hong Kong.; ShenZhen Hospital, The University of Hong Kong, Shenzhen, China., Ng IO; Department of Pathology, The University of Hong Kong, Hong Kong.; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong., Wong CC; Department of Pathology, The University of Hong Kong, Hong Kong.; ShenZhen Hospital, The University of Hong Kong, Shenzhen, China.; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong. |
المصدر: | Hepatology communications [Hepatol Commun] 2022 Jan; Vol. 6 (1), pp. 178-193. Date of Electronic Publication: 2021 Jul 21. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 101695860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2471-254X (Electronic) Linking ISSN: 2471254X NLM ISO Abbreviation: Hepatol Commun Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. Original Publication: [Hoboken, NJ] : Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases, [2017]- |
مواضيع طبية MeSH: | Carcinoma, Hepatocellular/*immunology , Cholangiocarcinoma/*immunology , Liver Neoplasms/*immunology , MARVEL Domain-Containing Proteins/*genetics , Programmed Cell Death 1 Receptor/*immunology, Animals ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Cells, Cultured ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/metabolism ; Hepatocytes ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; MARVEL Domain-Containing Proteins/antagonists & inhibitors ; Mice, Inbred C57BL ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Up-Regulation ; Mice |
مستخلص: | Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD-1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death-ligand 1 (PD-L1) found on cancer cells. Blocking PD-1/PD-L1 binding improves T-cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD-1/PD-L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti-PD-1/PD-L1 treatment. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) has been recently identified as a major regulator of PD-L1. Another member in the CMTM family, CKLF-like MARVEL transmembrane domain-containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD-L1 in the context of liver cancer. Up-regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD-L1 expression, hence facilitating escape from T cell-mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD-L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD-L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8 + T-cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti-PD-L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti-PD-L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti-PD-L1 immunotherapy in patients with liver cancer. (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.) |
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المشرفين على المادة: | 0 (CMTM4 protein, human) 0 (CMTM4 protein, mouse) 0 (Immune Checkpoint Inhibitors) 0 (MARVEL Domain-Containing Proteins) 0 (PDCD1 protein, human) 0 (Pdcd1 protein, mouse) 0 (Programmed Cell Death 1 Receptor) |
تواريخ الأحداث: | Date Created: 20210924 Date Completed: 20220304 Latest Revision: 20240226 |
رمز التحديث: | 20240226 |
مُعرف محوري في PubMed: | PMC8710793 |
DOI: | 10.1002/hep4.1682 |
PMID: | 34558800 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2471-254X |
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DOI: | 10.1002/hep4.1682 |