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Gohara, Yuma Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Tomonobu, Nahoko Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Kinoshita, Rie Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kaken ID researchmap
Futami, Junichiro Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University ORCID Kaken ID publons researchmap
Audebert, Léna Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Chen, Youyi Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Komalasari, Ni Luh Gede Yoni Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Jiang, Fan Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Yoshizawa, Chikako Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Murata, Hitoshi Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kaken ID publons researchmap
Yamamoto, Ken-ichi Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
Watanabe, Masami Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Kaken ID publons researchmap
Kumon, Hiromi Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University Kaken ID publons
Sakaguchi, Masakiyo Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine ORCID Kaken ID publons researchmap
Abstract
The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects.
Keywords
Breast cancer
REIC/Dkk-3
PD-L1
Immune checkpoint
Cancer therapy
Note
The version of record of this article, first published in Journal of Molecular Medicine, is available online at Publisher’s website: http://dx.doi.org/10.1007/s00109-023-02292-w
Published Date
2023-03-04
Publication Title
Journal of Molecular Medicine
Volume
volume101
Issue
issue4
Publisher
Springer Science and Business Media LLC
Start Page
431
End Page
447
ISSN
0946-2716
NCID
AA11034065
Content Type
Journal Article
language
English
OAI-PMH Set
岡山大学
Copyright Holders
© The Author(s) 2023
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PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1007/s00109-023-02292-w
License
http://creativecommons.org/licenses/by/4.0/
Citation
Gohara, Y., Tomonobu, N., Kinoshita, R. et al. Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. J Mol Med 101, 431–447 (2023). https://doi.org/10.1007/s00109-023-02292-w
Funder Name
Okayama University
Ministry of Education, Culture, Sports, Science and Technology
Japan Society for the Promotion of Science
Nagase Science and Technology Promotion Foundation
Momotaro-Gene Inc.
助成番号
20H03516