Abstract
Immature myeloid cells (IMCs) differentiate into dendritic cells, macrophages, and neutrophilsand are also considered to be precursors of MDSCs in tumor-bearing hosts. Recent studies suggest that the transcription factor CCAAT-enhancer-binding protein beta (C/EBP-β) plays a crucial role in MDSC expansion and function given that bone marrow cells lose their ability to differentiate into physiologically active MDSCs upon C/EBP-β deletion. Conversely, up-regulation of C/EBP-β can partially induce MDSC expansion through a mechanism that involves STAT3 (Condamine, et al, Trends in Immunology January 2011; Zhang, H, et al, Blood, October).
Epigenetic changes, such as histone acetylation status, have been recently shown to play a role in MDSC function (Youn JI, et al, Nature Immunology, 14 March 2013). The functional role of HDAC11, the newest member of the HDAC family was primarily unknown until our prior demonstration that this HDAC regulates IL-10 gene expression in mature myeloid cells. To determine whether HDAC11 might also play a role in immature myeloid cells and in the process of MDSC expansion, we recently utilized HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which enables us to identify dynamic changes in HDAC11 transcriptional activity (Heintz, N, et al, Nature Review Neuroscience, 2011 December). First, Ly6Chigh cells (M-MDSCs) have significantly lower expression of eGFP-HDAC11 when compared to Ly6G+ (G-MDSCs). Flow cytometric analysis revealed that expression of eGFP-HDAC11 further decreases in both Ly6G+ and Ly6Chigh compartments of tumor bearing TgHDAC11-eGFP mice, with greatest decrease in the Ly6Chigh (M-MDSCs) population, suggesting a role for HDAC11 in regulating MDSC expansion and function since M-MDSCs have been identified as the population that is more suppressive (Movahedi, K, et al, Blood, 2008).
Mechanistically, we have found for the first time, that this effect of HDAC11 upon MDSC function involves the regulatory machinery of C/EBP-β. First, at the steady state, bone marrow cells isolated from TgHDAC11-eGFP mice have an extremely high mRNA expression of C/EBP-β (120 fold unit difference) in the GR1+/eGFP-HDAC11+ (Ly6G+/G-MDSCs cells which also display high HDAC11 expression. Conversely, GR1+/eGFP-HDAC11- (Ly6Chigh/M-MDSCs) cells, which have minimal or absent HDAC11 expression also display minimal C/EBP-β mRNA expression. These results are recapitulated in the splenic compartment.
Interestingly, in EL4 tumor bearing TgHDAC11-eGFP mice there is higher expression of C/EBP-β in Ly6Chigh population compare with Ly6G+, with a 56 fold unit difference. Taken together, this data suggest that under tumor challenge, M-MDSCs have a higher expression of C/EBP-β when compared with G-MDSCs, which nominates HDAC11 as a regulator of C/EBP-β and the transition of Immature myeloid cells to functional MDSCs. A better understanding of this previously unknown role of HDAC11 in MDSC biology will ultimately lead to targeted epigenetic therapies to influence the suppressive abilities of these cells.
Disclosures:
Pinilla-Ibarz: BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau.
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