ID 113359
タイトル別表記
インターフェロン-γと協調したパノビノスタットによる骨髄腫細胞のPD-L1発現誘導
著者
岩佐, 昌美 徳島大学大学院医科学教育部(医学専攻)
Oda, Asuka Tokushima University
Bat-Erdene, Ariunzaya Tokushima University
Ashtar, Mohannad Tokushima University
Udaka, Kengo Tokushima University
Ozaki, Shuji Tokushima Prefectural Central Hospital
キーワード
Multiple myeloma
panobinostat
PD-L1
STAT1
IFN-γR1
資料タイプ
学位論文
抄録
Immunotherapy is revolutionizing the treatment paradigm for multiple myeloma (MM). Interferon (IFN)-γ is essential for immune responses, whereas immune checkpoint molecules, such as programmed cell death-1 ligand-1 (PD-L1), mitigate the beneficial anti-tumor immune responses. As HDAC inhibitors alter the immunogenicity and anti-tumor immune responses, we here explored the regulation of PD-L1 expression in MM cells by the clinically available HDAC inhibitor panobinostat in the presence of IFN-γ. IFN-γ activated the STAT1-IRF1 pathway to upregulate PD-L1 expression in MM cells, and panobinostat was able to upregulate their PD-L1 expression without activating the STAT1-IRF1 pathway. Of note, panobinostat enhanced IFN-γR1 expression, which substantially increased the total and phosphorylated levels of STAT1 protein but reduced IRF1 protein levels through proteasomal degradation in the presence of IFN-γ. Panobinostat further enhanced the IFN-γ-mediated durable STAT1 activation in MM cells; STAT1 gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-γ in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-γ-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-γ. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat.
掲載誌名
Oncotarget
ISSN
19492553
出版者
Impact Journals, LLC
10
20
開始ページ
1903
終了ページ
1917
発行日
2019-03-08
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Masami Iwasaの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
Copyright: Iwasa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3268号
学位記番号
甲医第1417号
学位授与年月日
2019-03-22
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
歯学系
医学系