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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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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DOI: https://doi.org/10.1007/s00262-016-1935-1