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HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells
- Source :
- Leukemia
- Publication Year :
- 2010
- Publisher :
- Springer Science and Business Media LLC, 2010.
-
Abstract
- LBH589 is a novel pan-histone deacetylase (HDAC) inhibitor that has potent antitumor activity in multiple myeloma and other hematological malignancies. However, its impact on the immune system has not been defined. We here evaluated the effects of LBH589 on human myeloid dendritic cells (DCs) at clinically relevant concentrations. Exposure to LBH589 affected the surface molecule expression on immature and mature DCs, which was associated with DC maturation (CD83↓), antigen presentation (human leukocyte antigen-ABC↓) and T-cell co-stimulation (CD40↓ and CD86↑). LBH589 decreased both protein and polysaccharide antigen uptake capacities by DCs. Importantly, LBH589 impaired DC function to stimulate antigen-specific immune responses, resulting in the significant reduction of invariant natural killer T-cell (CD1d-restricted) and T-cell (major histocompatibility complex-restricted) activation in innate and adaptive immunity. LBH589 also significantly repressed the production of interleukin (IL)-6, IL-10, IL-12p70, IL-23 and tumor necrosis factor-α by Toll-like receptor (TLR)3 and TLR4-induced DC activation, indicating an important role of HDAC activity in immune regulation and inflammation. RelB, a component of the nuclear factor-κ B signaling pathway, was the key component regulated by HDAC inhibition in DCs. Together, our preclinical study demonstrates that LBH589 significantly impairs the phenotype and function of DCs, indicating a need for monitoring the immune status in patients receiving HDAC inhibitor therapy. It also provides a rationale to evaluate LBH589 activity for the treatment of inflammation.
- Subjects :
- Cancer Research
Indoles
Antigen presentation
T cells
chemical and pharmacologic phenomena
invariant NKT cells
Biology
Hydroxamic Acids
Lymphocyte Activation
Article
NF-κB
chemistry.chemical_compound
Immune system
Histone Deacetylase Inhibitor
Panobinostat
Humans
Myeloid Cells
CD40 Antigens
Antigen-presenting cell
RELB
LBH589
NF-kappa B
hemic and immune systems
Dendritic Cells
Hematology
Dendritic cell
Natural killer T cell
Acquired immune system
Histone Deacetylase Inhibitors
Phenotype
Oncology
chemistry
Immunology
Cytokines
Natural Killer T-Cells
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....16aec3c2b9c0286eb76fd0f0c21354f8