Histone Deacteylase Inhibitors (HDACi) Suppress Toll-Like Receptor-Induced Dendritic Cell Maturation and Alter Secretion But Not Gene Expression Of Polarising Cytokines By Dendritic Cells

HDACi induce cancer cell apoptosis and are in use for T-cell lymphoma. Prior studies have indicated that HDACi are immune-suppressive. In this study, we address this issue by examining the effects of two different HDACi on human monocyte derived dendritic cell (hmDC) biology.

hmDC were activated by TLR stimuli (LPS or poly:IC). HDACi effect on TLR-induced hmDC activation was assessed by up regulation of co-stimulatory molecules CD80, CD86 and CD83 along with secretion of IL-12p70, IL-10 and IL1β. To address the mechanism for drug-induced altered cytokine secretion mRNA for IL-12p70, IL-10 and IL1β were assessed followed by mir-155 mRNA and SOCS-1 protein. The functional outcome was assessed in an allogeneic MLR.

At doses sub-optimal to induce myeloma cell death, both drugs significantly inhibited TLR-induced hmDC increase in CD80 and CD83, but not CD86. TLR-induced secretion of IL-10 and IL12p70 was reduced while IL-1β secretion was increased. This occurred regardless of drug sequencing. HDACi did not significantly alter expression of IL-12p70, IL-10 or IL-1β mRNA despite changes in protein levels. To reveal the mechanism for the HDACi-induced hmDC IL-12p70 defect, the upstream molecules miR-155 and SOCS-1 were examined. Interestingly, panobinostat but not romidepsin induced mir-155 down-regulation and SOCS-1 protein increase. Subsequently, allogeneic T-cells co-cultured with HDACi/TLR-ligand-treated hmDC secreted lower levels of cytokines (decreased secretion of IFN-γ, IL-2, TNF, IL-4 and IL-17) compared to those allogeneic T cells co-cultured with control hmDC.

In this study, we show that whilst HDACi impair DC maturation and modulate subsequent T cell responses. Our findings suggest that panobinostat induces the IL-12p70 effect via the mir-155/SOCS-1 pathway, whereas romidepsin induces the effect via a mir-155 independent pathway. This data suggests that HDACi affect the hmDC maturation response to pathogen, and that these drugs may alter the ability of treated patients to raise an effective immune response to pathogens or, indeed, tumour antigens.

No relevant conflicts of interest to declare.