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ID 113359
Title Alternative
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
Author
Iwasa, Masami Tokushima University
Oda, Asuka Tokushima University
Bat-Erdene, Ariunzaya Tokushima University
Ashtar, Mohannad Tokushima University
Sogabe, Kimiko Tokushima University
Udaka, Kengo Tokushima University
Ozaki, Shuji Tokushima Prefectural Central Hospital
Keywords
Multiple myeloma
panobinostat
PD-L1
STAT1
IFN-γR1
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Oncotarget
ISSN
19492553
Publisher
Impact Journals, LLC
Volume
10
Issue
20
Start Page
1903
End Page
1917
Published Date
2019-03-08
Remark
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。
Rights
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3268号
Diploma Number
甲医第1417号
Granted Date
2019-03-22
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Oral Sciences
Medical Sciences