PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-γ
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Masami Iwasa1, Takeshi Harada1, Asuka Oda1, Ariunzaya Bat-Erdene1, Jumpei Teramachi2, Hirofumi Tenshin3, Mohannad Ashtar3, Masahiro Oura1, Kimiko Sogabe1, Kengo Udaka1, Shiro Fujii1, Shingen Nakamura1, Hirokazu Miki4, Kumiko Kagawa1, Shuji Ozaki5 and Masahiro Abe1
1Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
2Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
3Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan
4Division of Transfusion Medicine and Cell therapy, Tokushima University Hospital, Tokushima, Japan
5Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Tokushima, Japan
Masahiro Abe, email: firstname.lastname@example.org
Keywords: multiple myeloma; panobinostat; PD-L1; STAT1; IFN-γR1
Received: September 26, 2018 Accepted: February 15, 2019 Published: March 08, 2019
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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