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Article: Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell–Mediated Antitumor Immunity Through PD-L1

TitleInhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell–Mediated Antitumor Immunity Through PD-L1
Authors
Issue Date2021
PublisherWiley Open Access. The Journal's web site is located at http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2471-254X/
Citation
Hepatology Communications, 2021, Epub 2021-07-21 How to Cite?
AbstractLiver 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.
Persistent Identifierhttp://hdl.handle.net/10722/304798
ISSN
2023 Impact Factor: 5.6
2023 SCImago Journal Rankings: 2.217
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChui, NQN-
dc.contributor.authorCheu, JWS-
dc.contributor.authorYuen, VWH-
dc.contributor.authorChiu, DKC-
dc.contributor.authorGoh, CC-
dc.contributor.authorLee, D-
dc.contributor.authorZhang, MS-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CCL-
dc.date.accessioned2021-10-05T02:35:21Z-
dc.date.available2021-10-05T02:35:21Z-
dc.date.issued2021-
dc.identifier.citationHepatology Communications, 2021, Epub 2021-07-21-
dc.identifier.issn2471-254X-
dc.identifier.urihttp://hdl.handle.net/10722/304798-
dc.description.abstractLiver 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.-
dc.languageeng-
dc.publisherWiley Open Access. The Journal's web site is located at http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2471-254X/-
dc.relation.ispartofHepatology Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleInhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell–Mediated Antitumor Immunity Through PD-L1-
dc.typeArticle-
dc.identifier.emailLee, D: leederek@hku.hk-
dc.identifier.emailZhang, MS: mistyzs@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityWong, CCL=rp01602-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/hep4.1682-
dc.identifier.scopuseid_2-s2.0-85110989332-
dc.identifier.hkuros325809-
dc.identifier.hkuros327387-
dc.identifier.volumeEpub 2021-07-21-
dc.identifier.isiWOS:000675131100001-
dc.publisher.placeUnited Kingdom-

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