Abstract 5595: HDAC inhibitor Entinostat disrupts function of PMN-MDSC
Authors: Ayumi Hashimoto, Vinit Kumar, Peter Ordentlich, Dmitry I. Gabrilovich
Journal: Cancer Research (2017)

Abstract Myeloid-derived suppressor cells (MDSCs), consisting of subpopulations of polymorphonuclear (PMN; CD11b+Ly6G+Ly6Clo) and monocytic (M; CD11b+Ly6G-Ly6Chi) MDSCs play a major role as immune suppressors in cancer. MDSC-targeted therapy has not been developed yet. Histone deacetylases (HDAC) are critically involved in epigenetic regulation of multiple genes and may regulate MDSC number and function. The purpose of this study was to evaluate the effect of the class I HDAC inhibitor, entinostat on differentiation and function of MDSCs in mouse tumor models of lung cancer (Lewis Lung Carcinoma, LLC) and colon cancer (CT26). LLC and CT26 tumor-bearing mice were treated with entinostat (10 mg/kg, p.o. daily for two weeks). Entinostat caused significant increase in the presence of CD45+ CD11b+ myeloid cells in bone marrow, spleen and tumors. This increase was largely due to accumulation of Ly6ClowLy6G+ PMN. Unexpectedly, this was associated with a small decrease in the presence of common myeloid progenitor (CMP) and granulocyte-macrophage progenitor (GMP) cells in bone marrow. This suggests that entinostat affects differentiation of PMN downstream of GMP. Experiments in vitro demonstrated that entinostat increased differentiation of enriched hematopoietic progenitor cells (HPC) to PMN in the presence of tumor explant supernatant (TES), which supported the in vivo result. To assess the effect of entinostat on the function of PMN-MDSCs, Ly6G+ cells were purified from spleen and tumor of LLC tumor-bearing mice treated with entinostat or vehicle alone and tested for their ability to suppress antigen-specific T cell. As expected Ly6G+ PMN-MDSC from tumor-bearing mice treated with vehicle alone had strong suppressive activity. In contrast, Ly6G+ cells from spleen and tumor of entinostat-treated LLC tumor-bearing mice show significantly reduced suppressive activity. This result was confirmed in experiments with Ly6G+ cells differentiated from HPC culture with/without entinostat treatment. To determine whether entinostat inhibition of PMN-MDSC immunosuppressive function could enhance immune checkpoint activity, entinostat combined with an anti-PD-1 antibody was evaluated using the LLC tumor-bearing mice. These mice were treated with entinostat (10 mg/kg, p.o., daily) and anti-mouse PD-1 rat antibody (10 mg/kg, i.p., twice a week). Entinostat or PD-1 antibody alone did not significantly inhibit the tumor growth. In striking contrast, the combination treatment blocked tumor progression. Our data demonstrate that entinostat increases a population of PMN-MDSCs that are no longer immunosuppressive leading to enhanced anti-tumor activity when combined with an immune checkpoint inhibitor. This novel phenomenon provides further rationale for combination therapy of entinostat with anti-PD-1 antibody or other checkpoint inhibitors in clinical settings. Citation Format: Ayumi Hashimoto, Vinit Kumar, Peter Ordentlich, Dmitry I. Gabrilovich. HDAC inhibitor Entinostat disrupts function of PMN-MDSC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5595. doi:10.1158/1538-7445.AM2017-5595