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Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer

Nature Immunology volume 14, pages 211–220 (2013)Cite this article

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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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Figure 1: MDSC populations in tumor-bearing mice.
Figure 2: Differentiation of PMN-MDSCs from M-MDSCs in vitro.
Figure 3: Differentiation of PMN-MDSCs from M-MDSCs in vivo.
Figure 4: Expression of retinoblastoma in MDSCs.
Figure 5: Association of Rb1 with subset of M-MDSCs.
Figure 6: PMN-MDSCs and M-MDSCs in cancer patients.
Figure 7: Retinoblastoma and regulation of myeloid differentiation in cancer.
Figure 8: Role of HDAC-2 in silencing Rb1 in MDSCs.

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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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Authors and Affiliations

  1. Departments of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Je-In Youn, Vinit Kumar, Michelle Collazo, Yulia Nefedova, Thomas Condamine, Pingyan Cheng, Alejandro Villagra, Eduardo Sotomayor & Dmitry I Gabrilovich

  2. Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Alejandro Villagra, Pedro Horna & Eduardo Sotomayor

  3. Department of Oncologic Sciences, University of South Florida, Tampa, Florida, USA

    Alejandro Villagra, Scott Antonia, Judith C McCaffrey, Mayer Fishman, Eduardo Sotomayor & Dmitry I Gabrilovich

  4. Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Scott Antonia & Dmitry I Gabrilovich

  5. Otolaryngology–Head and Neck Surgery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Judith C McCaffrey

  6. Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Mayer Fishman

  7. Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

    Amod Sarnaik

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  1. Je-In Youn
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Contributions

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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Correspondence to Dmitry I Gabrilovich.

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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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