Histone Deacetylase 11 (HDAC11) As a Novel Transcriptional Regulator of C/EBP-β, in Immature Myeloid Cell to Myeloid Derived Suppressor Cell Transition
Authors: Chen Jie , Sahakian Eva , Powers John J. , LienlafMoreno Maritza , Xing Limin , Deng Susan , Distler Allison , Cheng Fengdong , Villagra Alejandro , Horna Pedro , Sotomayor Eduardo M. , Pinilla-Ibarz Javier 
Published: October 2019

In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, dendritic cells, and neutrophils. However, in pathological conditions such as in cancer, these immature cells differentiate into myeloid derived suppressor cells (MDSCs). Transcription factor CCAAT-enhancer-binding protein beta (C/EBP-β) plays a crucial role in the accumulation of MDSCs in several pathological conditions. Of note, mice lacking C/EBP-β in the bone marrow compartment lose the ability to differentiate IMCs into pathologically active MDSCs2.In contrast, up-regulation of C/EBP-β can partly induce MDSC expansion through a mechanism involving the STAT3 pathway3.

Epigenetic changes, such as histone acetylation status, have been recently shown to modulate the regulatory function of MDSCs4. However, the epigenetic mechanism(s) involved in regulation of C/EBP-β gene expression in MDSCs are poorly understood. Here we show for the first time that among all the HDACs known, HDAC11, the newest member of this family of enzymes, is recruited to the C/EBP-β gene promoter region of primary myeloid cells isolated from C57BL/6 mice. Such a finding led us to explore the functional consequences of disrupting HDAC11 in myeloid cells. First, we observed a markedly higher expression of C/EBP-β mRNA (194 fold difference) in the CD11b+/Ly6G+ granulocytic compartment and a 6.7 fold difference in the CD11b+/Ly6C+monocytic compartments of HDAC11KO mice relative to control wild type mice. Second, MDSCs from HDAC11 KO mice display a higher suppressive phenotype and mechanistically we have found that they have increased expression of the immunosuppressive STAT3/IL10 axis. Third, inoculation of EL4 tumor cells into HDAC11KO mice and controls resulted in a higher expansion capacity of splenic MDSCs in mice devoid of HDAC11. Such an effect was associated with a more rapid tumor growth in HDAC11KO mice as compared to WT mice. Similar aggressive tumor growth was also observed in HDAC11 myeloid conditional KO mice (LyZ-Cre-HDAC11KO).

Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of C/EBP-β in MDSCs. Indeed, in the absence of this epigenetic checkpoint of C/EBP-β gene expression, the fully suppressive potential of MDSCs was fully unleashed. A better understanding of this novel role of HDAC11 in myeloid biology will ultimately lead to targeted epigenetic therapies to manipulate the suppressive abilities of these immunoregulatory cells.

1. Hirai H, Zhang P, Dayaram T, et al. C/EBPbeta is required for 'emergency' granulopoiesis. Nat Immunol 2006; 7(7): 732-9.

2. Marigo I, Bosio E, Solito S, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 2010; 32(6): 790-802.

3. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011; 32(1): 19-25.

4. Youn JI, Kumar V, Collazo M, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 2013; 14(3): 211-20.

Disclosures

No relevant conflicts of interest to declare.