Abstract 4260: Histone deacetylase 11 (HDAC11) as a novel therapeutic target in the regulation of myeloid-derived suppressor cell (MDSC)

Abstract

Abstract The physiological role of this HDAC11, the newest member of the HDAC family was mainly unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro. To better elucidate the role of HDAC11 in these cells, we have utilized 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 macrophages, dendritic cells, 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 EL4 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 extent 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, with greatest decrease in the Ly6Chigh population 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 nontransgenic mice also demonstrated that tumor derived MDSCs display less HDAC11 mRNA expression compared to splenic MDSCs, with lowest expression of HDAC11 in the Ly6Chigh MDSCs. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our preliminary functional studies in TgHDAC11-eGFP mice which demonstrates that isolated GR1+/eGFP- cells demonstrate more suppressive phenotype than that of GR1+/eGFP+ cells, in the presence of tumor challenge. Taken together, these results suggest that HDAC11 plays a regulatory role in the expansion and function of MDSCs 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 malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4260. doi:1538-7445.AM2012-4260