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Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors

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Abstract

Myeloid-derived suppressor cells (MDSCs) are widely implicated in negative regulation of immune responses in cancer. Inhibition of class I histone deacetylases (HDAC) with entinostat has anti-MDSC activity. However, as single agent, it did not delay tumor growth in EL4 and LLC tumor models. Here, we found that entinostat reduced immune suppressive activity of only one type of MDSC—polymorphonuclear, PMN-MDSC, whereas it had no effect on monocytic M-MDSC or macrophages. M-MDSC had high amount of class II HDAC—HDAC6, which was further increased after the treatment of mice with entinostat. Inhibition of HDAC6 with ricolinostat reduced suppressive activity of M-MDSC, but did not affect PMN-MDSC or delayed tumor growth. However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.

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Funding

This work was supported by Syndax Pharmaceuticals and by animal, genomics, and flow cytometry core facilities of Wistar Cancer Center Support NIH Grant P50 CA168536. All authors state no competing financial interests.

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Authors and Affiliations

  1. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Rm. 118, 3601 Spruce Str., Philadelphia, PA, 19104, USA

    Ayumi Hashimoto & Dmitry Gabrilovich

  2. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA

    Takeshi Fukumoto & Rugang Zhang

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  1. Ayumi Hashimoto
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  2. Takeshi Fukumoto
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  4. Dmitry Gabrilovich
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Correspondence to Dmitry Gabrilovich.

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All procedures were performed and approved in strict accordance with the Institutional Animal Care and Use Committee (IACUC) at the Wistar Institute, and with the NIH Guide for the Care and Use of Laboratory Animal guidelines.

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Hashimoto, A., Fukumoto, T., Zhang, R. et al. Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors. Cancer Immunol Immunother 69, 1929–1936 (2020). https://doi.org/10.1007/s00262-020-02588-7

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  • DOI: https://doi.org/10.1007/s00262-020-02588-7

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