Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a...

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Published in:Cell reports (Cambridge) Vol. 33; no. 13; p. 108571
Main Authors: Kwak, Taekyoung, Wang, Fang, Deng, Hui, Condamine, Thomas, Kumar, Vinit, Perego, Michela, Kossenkov, Andrew, Montaner, Luis J., Xu, Xiaowei, Xu, Wei, Zheng, Cathy, Schuchter, Lynn M., Amaravadi, Ravi K., Mitchell, Tara C., Karakousis, Giorgos C., Mulligan, Charles, Nam, Brian, Masters, Gregory, Hockstein, Neil, Bennett, Joseph, Nefedova, Yulia, Gabrilovich, Dmitry I.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 29.12.2020
Subjects:
immune suppression
myeloid-derived suppressor cells
S100A9
tumor associated macrophages
tumor immunology
tumor associated macrophages
tumor immunology
immune suppression
S100A9
myeloid-derived suppressor cells
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Summary:Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPβ. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting. [Display omitted] •M-MDSCs, in contrast to monocytes, differentiate into immune-suppressive macrophages•M-MDSC-derived macrophages fail to downregulate expression of S100A8/A9 proteins•High expression of S100A9 regulates suppressive activity of macrophages via C/EBPβ•S100A9+ macrophages are associated with negative clinical outcome in cancer patients Kwak et al. report that tumor immune-suppressive macrophages differentiate from the population of myeloid-derived suppressor cells (MDSCs). This effect is dependent on the persistent expression of S100A9 protein. The presence of S100A9-positive macrophages in tumors is associated with shorter survival and poor response to immunotherapy of cancer patients.
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T.K. and F.W. conducted experiments, analyzed data, and wrote the manuscript. H.D., T.C., V.K., and M.P. conducted experiments. A.K. analyzed data. X.X., W.X., C.Z., L.M.S., R.K.A., T.C.M., G.C.K., C.M., B.N., G.M., N.H., J.B., and L.J.M. provided materials and data analysis. Y.N. acquired funding and wrote the manuscript. D.I.G. designed experiments, analyzed data, wrote the manuscript, and acquired funding.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108571