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Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro

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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.

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Abbreviations

Arg-1:

Arginase-1

BM:

Bone marrow

CFSE:

Carboxyfluorescein diacetate succinimidyl ester

CTL:

Cytotoxic T lymphocyte

DCFH-DA:

2′,7′ Dichlorodihydrofluorescein diacetate

GM-CSF:

Granulocyte-macrophage colony stimulating factor

HDACi:

Histone deacetylase inhibitor(s)

IDO:

Indoleamine 2,3-dioxygenase

iNOS:

Inducible nitric oxide synthase

iTreg:

Inducible regulatory T cell

l-NMMA:

l-NG-monomethyl-arginine

MDSC:

Myeloid-derived suppressor cell(s)

NaB:

Sodium butyrate

NAC:

N-Acetylcysteine

nor-NOHA:

N ω-Hydroxy-nor-l-arginine

PBMC:

Peripheral blood mononuclear cell(s)

ROS:

Reactive oxygen species

SAHA:

Suberoylanilide hydroxamic acid

SPC:

Spleen cell(s)

TCR:

T cell receptor

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81272311, 81273538 and 81472643) and Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, No. 20130171110056). We thank Dr. Gendie E. Lash for her contribution in revising the manuscript.

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Authors and Affiliations

  1. 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

    Hai-Fang Wang, Zi-Qian Li, Yi-Fei Qi, Ge Zhang, Hong-Sheng Wang & Jun Du

  2. Guangzhou Institute of Pediatrics, Department of Obstetrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

    Fen Ning

  3. The Laboratory of Endocrinology and Metabolism, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

    Zong-Cai Liu

  4. Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Tianhe District, Guangzhou, 510632, People’s Republic of China

    Long Wu & Shao-Hui Cai

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  1. Hai-Fang Wang
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Wang, HF., Ning, F., Liu, ZC. et al. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro. Cancer Immunol Immunother 66, 355–366 (2017). https://doi.org/10.1007/s00262-016-1935-1

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