title: HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.forename: Y-T
authors.initials: YT
authors.lastname: Tai
authors.forename: Z
authors.initials: Z
authors.lastname: Tian
authors.forename: T
authors.initials: T
authors.lastname: Hideshima
authors.forename: D
authors.initials: D
authors.lastname: Chauhan
authors.forename: P
authors.initials: P
authors.lastname: Nanjappa
authors.forename: M A
authors.initials: MA
authors.lastname: Exley
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D019013:CD40 Antigens / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D008213:Lymphocyte Activation / Q000187:drug effects; D022423:Myeloid Cells / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D000077767:Panobinostat; D010641:Phenotype
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D016328:NF-kappa B; D000077767:Panobinostat