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PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ

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 alte...

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Autores principales: Iwasa, Masami, Harada, Takeshi, Oda, Asuka, Bat-Erdene, Ariunzaya, Teramachi, Jumpei, Tenshin, Hirofumi, Ashtar, Mohannad, Oura, Masahiro, Sogabe, Kimiko, Udaka, Kengo, Fujii, Shiro, Nakamura, Shingen, Miki, Hirokazu, Kagawa, Kumiko, Ozaki, Shuji, Abe, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443002/
https://www.ncbi.nlm.nih.gov/pubmed/30956773
http://dx.doi.org/10.18632/oncotarget.26726
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author Iwasa, Masami
Harada, Takeshi
Oda, Asuka
Bat-Erdene, Ariunzaya
Teramachi, Jumpei
Tenshin, Hirofumi
Ashtar, Mohannad
Oura, Masahiro
Sogabe, Kimiko
Udaka, Kengo
Fujii, Shiro
Nakamura, Shingen
Miki, Hirokazu
Kagawa, Kumiko
Ozaki, Shuji
Abe, Masahiro
author_facet Iwasa, Masami
Harada, Takeshi
Oda, Asuka
Bat-Erdene, Ariunzaya
Teramachi, Jumpei
Tenshin, Hirofumi
Ashtar, Mohannad
Oura, Masahiro
Sogabe, Kimiko
Udaka, Kengo
Fujii, Shiro
Nakamura, Shingen
Miki, Hirokazu
Kagawa, Kumiko
Ozaki, Shuji
Abe, Masahiro
author_sort Iwasa, Masami
collection PubMed
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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spelling pubmed-64430022019-04-05 PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ Iwasa, Masami Harada, Takeshi Oda, Asuka Bat-Erdene, Ariunzaya Teramachi, Jumpei Tenshin, Hirofumi Ashtar, Mohannad Oura, Masahiro Sogabe, Kimiko Udaka, Kengo Fujii, Shiro Nakamura, Shingen Miki, Hirokazu Kagawa, Kumiko Ozaki, Shuji Abe, Masahiro Oncotarget Research Paper 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. Impact Journals LLC 2019-03-08 /pmc/articles/PMC6443002/ /pubmed/30956773 http://dx.doi.org/10.18632/oncotarget.26726 Text en Copyright: © 2019 Iwasa et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Iwasa, Masami
Harada, Takeshi
Oda, Asuka
Bat-Erdene, Ariunzaya
Teramachi, Jumpei
Tenshin, Hirofumi
Ashtar, Mohannad
Oura, Masahiro
Sogabe, Kimiko
Udaka, Kengo
Fujii, Shiro
Nakamura, Shingen
Miki, Hirokazu
Kagawa, Kumiko
Ozaki, Shuji
Abe, Masahiro
PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title_full PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title_fullStr PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title_full_unstemmed PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title_short PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
title_sort pd-l1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443002/
https://www.ncbi.nlm.nih.gov/pubmed/30956773
http://dx.doi.org/10.18632/oncotarget.26726
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