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