Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model

• Material Type: 博士論文
• Title: Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model
• Author/Editor: Yamaguchi, Izumi; Nakajima, Kohei; Shono, Kenji; Mizobuchi, Yoshifumi; Fujihara, Toshitaka; Shikata, Eiji; Yamaguchi, Tadashi; Kitazato, Keiko; Sampetrean, Oltea; Saya, Hideyuki; Takagi, Yasushi
• Author Heading: Yamaguchi, Izumi; Nakajima, Kohei; Shono, Kenji; Mizobuchi, Yoshifumi; Fujihara, Toshitaka; Shikata, Eiji; Yamaguchi, Tadashi; Kitazato, Keiko; Sampetrean, Oltea; Saya, Hideyuki; Takagi, Yasushi
• Publication, Distribution, etc.: Oxford University Press|the Society for Neuro-Oncology|the European Association of Neuro-Oncology
• Publication Date: 2019-12-26
• Publication Date (W3CDTF): 2019-12-26
• Alternative Title: セレコキシブによるFKBP5を介したPD-L1の発現低下は, 悪性神経膠腫モデルにおける抗PD-1抗体医薬による抗腫瘍効果を増強する; FKBP5 regulation on anti-PD-1 therapy
• Periodical title: Neuro-Oncology Advances
• No. or year of volume/issue: 2 1
• Volume: 2
• Issue: 1
• Pages: vdz058-
• ISSN (Periodical Title): ISSN : 2632-2498
• Degree grantor/type: 徳島大学
• Date Granted: 2020-03-23
• Dissertation Number: 甲第3370号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: glioblastoma; PD-1; PD-L1; FKBP5; celecoxib
• Target Audience: 一般
• Note (General): Background. Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods. Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results. Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions. Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [e-mail]
• Related Material (DOI): 10.1093/noajnl/vdz058
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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