HDAC11 regulates expression of C/EBPβ and immunosuppressive molecules in myeloid-derived suppressor cells

Abstract

Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells derived from bone marrow and negatively regulate both innate and adaptive immunity in the tumor microenvironment. Previously we have demonstrated that MDSCs lacking histone deacetylase 11 (HDAC11) displayed an increased suppressive activity against CD8 + T-cells. However, the mechanisms of HDAC11 that contribute to the suppressive function of MDSCs remain unclear. Here, we show that arginase activity and NO production is significantly higher in HDAC11 knockout MDSCs when compared with wild-type (WT) controls. In the absence of HDAC11, elevated arginase level and enzymatic activity were observed preferentially in the tumorinfiltrated granulocytic MDSCs, whereas iNOS expression and NO production were increased in the tumor-infiltrated monocytic MDSCs. Of note and for the first time, we demonstrated an association between the elevated expression of immunosuppressive molecules with up-regulation of the transcription factor C/EBPβ in MDSCs lacking HDAC11. Interestingly, the highest expression of C/EBPβ was observed among CD11b + Gr-1 + MDSCs isolated from tumor-bearing mice. The additional demonstration that HDAC11 is recruited to the promoter region of C/EBPβ in WT MDSCs suggests a novel molecular mechanism by which HDAC11 influence the expression of immunosuppressive molecules in MDSCs through regulation of C/EBPβ gene expression.

HDAC11 negatively regulates antifungal immunity by inhibiting Nos2 expression via binding with transcriptional repressor STAT3

“…The functions of HDAC11 in innate and adaptive immune cells have been extensively studied by using deficient mice [ 16 , 21 , 23 , 24 , 44 ]. Recently, there has been increasing interests in the role of HDAC11 in regulating pro-inflammatory and anti-inflammatory effects in different immune cells.…”

“…In macrophages, HDAC11 is a negative regulator of the anti-inflammatory cytokine IL-10, and HDAC11 knockdown cells manifest immune tolerance phenotype [ 23 ]. Myeloid-derived suppressor cells (MDSCs) lacking HDAC11 displayed an increased suppressive activity against CD8 + T-cells [ 44 ]. Conversely, deletion of HDAC11 in T cells promotes pro-inflammatory Th1 cell differentiation and enhanced effector T cell responses [ 24 ].…”

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases

“…HDAC2 facilitates the conversion from M-MDSCs to PMN-MDSCs as it directly binds to retinoblastoma gene (rb1) promoter and causes silencing of rb1 expression in cancer (50). A recently identified member of the HDAC family named HDAC11 mediates expression of C/EBPb and some other immunosuppressive molecules in MDSCs (51,52). Jie Chen et al reported that if without HDAC11, the arginase level and enzymatic activity would be significantly higher in the tumor-infiltrated PMN-MDSCs, whereas iNOS expression and NO production were observed to be significantly higher in the tumor-infiltrated M-MDSCs compared with wild-type (WT) controls.…”

Acetylation in Tumor Immune Evasion Regulation

“…HDAC10 deletion Treg exhibited a stronger immune inhibitory effect and represses inflammation after intracerebral hemorrhage ( Dahiya et al, 2020 ). MDSCs without HDAC11 exhibit stronger inhibitory activity against CD8+T cells via inducing high level of immunosuppressive enzymes expressed in CD8+T cells ( Chen et al, 2021 ).…”