Abstract
Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
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CD8-Positive T-Lymphocytes / immunology
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Carcinogenesis / genetics
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Caspase 8 / metabolism
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Lineage / genetics
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Coculture Techniques
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / metabolism
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Granulocytes / physiology*
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Immune Tolerance / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Minor Histocompatibility Antigens
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Monocytes / physiology*
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Myeloid Cells / physiology*
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Neoplasm Transplantation
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Neoplasms, Experimental / immunology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction / genetics
Substances
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BCL2-related protein A1
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Cflar protein, mouse
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Mcl1 protein, mouse
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Caspase 8
Associated data
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GEO/GSE59047
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GEO/GSE61479