A Novel Role of Histone Deacetylase 11 (HDAC11) in Regulation of Myeloid-Derived Suppressor Cell (MDSC) Expansion

Abstract 2439

HDAC11 is the newest member of the HDAC family. The physiological role of this HDAC was largely unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro¹. To better elucidate the role of HDAC11 in these cells, we have utilized an HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression /transcriptional activity in immune cells in vivo.

Immature myeloid cells (IMCs) differentiate into dendritic cells, macrophages, and neutrophils and are also considered to be precursors of MDSCs in tumor-bearing hosts. Here, we show for the first time that HDAC11 plays an important role in this process. First, IMCs from the bone marrow and spleen of TgHDAC11-eGFP mice display high expression of eGFP indicative of HDAC11 transcriptional activation in these cells in the steady state. Subcutaneous injection of PANCO2 tumor cells into these mice resulted in expansion of MDSCs (identified by the expression of CD11b+/GR1+ [Ly6G and Ly6C] with variable expression of CD49d and CD115) in their lymphoid organs which was similar in magnitude to the expansion observed in tumor-bearing wild type (WT) mice. Of note, flow cytometric analysis revealed that expression of eGFP was significantly decreased in the myeloid compartment of tumor bearing TgHDAC11-eGFP mice, suggesting that the transition of IMC into MDSCs might require a decrease in HDAC11 expression. Reminiscent of our findings in the eGFP mice, studies in non-transgenic mice also demonstrated that tumor derived CD11b+ Ly6G+ MDSCs display less HDAC11 mRNA expression. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our studies in HDAC11KO mice, demonstrating the acquisition of a suppressive cell phenotype, by myeloid cells identical to MDSCs, in the steady state and in the absence of tumor challenge.

Taken together, HDAC11 might function as a negative regulator of MDSC expansion/function in vivo. A better understanding of this previously unknown role of HDAC11 in MDSC biology might lead to targeted epigenetic therapies to influence the suppressive abilities of these cells and augment the efficacy of immunotherapeutic approaches against hematologic malignancies.

1. Villagra A, et al. Nat Immunol. 2009 Jan;10(1):92-100