Abstract
Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6ChiLy6G− inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.
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Acknowledgements
We thank A. Beg (H. Lee Moffitt Cancer Center) for providing us with Kras/mCC10 mice and D.J. McCance (Queen's University Belfast, UK) for providing us with Ad-Rb1 vectors. This work was supported by US National Institutes of Health grant CA84488.
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J.-I.Y. participated in design and performed most of the experiments evaluating MDSCs, V.K. and M.C. did most of the experiments assessing Rb1; Y.N., T.C., P.C. performed some of the experiments; A.V. assisted in experiments with HDAC and provided advice; P.H. performed cytological evaluation of the samples; S.A., J.C.M., M.F., A.S. and E.S. provided human samples and advice. D.I.G. designed most of the experiments, analyzed the data and together with J.-I.Y., Y.N. and T.C. wrote the paper.
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Youn, JI., Kumar, V., Collazo, M. et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol 14, 211–220 (2013). https://doi.org/10.1038/ni.2526
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DOI: https://doi.org/10.1038/ni.2526
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