title: Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.
abstract: Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells that suppress anti-tumor immunity. MDSC are increased in tumor-bearing hosts; thus, depletion of MDSC may enhance anti-tumor immunity. Histone deacetylase inhibitors (HDACi) are chemical agents that are primarily used against hematologic malignancies. The ability of these agents to modulate anticancer immunity has recently been extensively studied. However, the effect of HDACi on MDSC has remained largely unexplored. In the present study, we provide the first demonstration that HDACi treatment decreases MDSC accumulation in the spleen, blood and tumor bed but increases the proportion of T cells (particularly the frequency of IFN-γ- or perforin-producing CD8+T cells) in BALB/C mice with 4T1 mammary tumors. In addition, HDACi exposure of bone marrow (BM) cells significantly eliminated the MDSC population induced by GM-CSF or the tumor burden in vitro, which was further demonstrated as functionally important to relieve the inhibitory effect of MDSC-enriched BM cells on T cell proliferation. Mechanistically, HDACi increased the apoptosis of Gr-1+cells (almost MDSC) compared with that of Gr-1-cells, which was abrogated by the ROS scavenger N-acetylcysteine, suggesting that the HDACi-induced increase in MDSC apoptosis due to increased intracellular ROS might partially account for the observed depletion of MDSC. These findings suggest that the elimination of MDSC using an HDACi may contribute to the overall anti-tumor properties of these agents, highlighting a novel property of HDACi as potent MDSC-targeting agents, which may be used to enhance the efficacy of immunotherapeutic regimens.
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China.
authors.forename: Hai-Fang
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Guangzhou Institute of Pediatrics, Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Ning
authors.affiliation: The Laboratory of Endocrinology and Metabolism, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
authors.forename: Zong-Cai
authors.initials: ZC
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Tianhe District, Guangzhou, 510632, People's Republic of China.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China.
authors.forename: Zi-Qian
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Qi
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Tianhe District, Guangzhou, 510632, People's Republic of China. csh5689@sina.com.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Cai
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, No. 132 Waihuan East Road, University Town, Guangzhou, 510006, People's Republic of China. dujun@mail.sysu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D056572:Histone Deacetylase Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Apoptosis; Histone deacetylase inhibitors; MDSC; ROS; Sodium butyrate; Vorinostat