Dataset Information

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

ABSTRACT: Immunotherapy is revolutionizing the treatment paradigm for multiple myeloma (MM). Interferon (IFN)-? 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-?. IFN-? 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-?R1 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-?. Panobinostat further enhanced the IFN-?-mediated durable STAT1 activation in MM cells; STAT1 gene silencing abolished the PD-L1 upregulation by panobinostat and IFN-? in combination, indicating a critical role for STAT1. These results suggest that panobinostat enhances PD-L1 expression by facilitating the IFN-?-STAT1 pathway in a ligand-dependent manner in MM cells with ambient IFN-?. PD-L1 upregulation should be taken into account when combining immunotherapies with panobinostat.

SUBMITTER: Iwasa M

PROVIDER: S-EPMC6443002 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Iwasa Masami M Harada Takeshi T Oda Asuka A Bat-Erdene Ariunzaya A Teramachi Jumpei J Tenshin Hirofumi H Ashtar Mohannad M Oura Masahiro M Sogabe Kimiko K Udaka Kengo K Fujii Shiro S Nakamura Shingen S Miki Hirokazu H Kagawa Kumiko K Ozaki Shuji S Abe Masahiro M

Oncotarget 20190308 20

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. ...[more]

PMID: 30956773

Similar Datasets

Project description:BackgroundPD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies.MethodsThe distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival.ResultsThe distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-γ level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-γ induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-γ-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-γ level. By combining the relative expression of the listed IFN-γ-induced genes, IFN-γ score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies.ConclusionOur study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-γ is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-γ score aggregated from the expressions of the listed IFN-γ-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets