Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer
TL;DR: It is shown that a large proportion of M-M DSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs, and this acquisition was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2).
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, Ly6C(hi)Ly6G(-) 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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University of Verona1, University of Duisburg-Essen2, Icahn School of Medicine at Mount Sinai3, University of Milan4, New York University5, University of Padua6, St. Jude Children's Research Hospital7, Louisiana State University8, University of Maryland, Baltimore County9, Georgia Regents University10, University of Eastern Piedmont11, Heidelberg University12, German Cancer Research Center13, University of Pennsylvania14, Wistar Institute15
TL;DR: The authors identify the challenges and proposed set of minimal reporting guidelines for mouse and human MDSC are a heterogeneous population expanded in cancer and other chronic inflammatory conditions.
Abstract: Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
1,869 citations
TL;DR: Current understanding is discussed as to the nature of differences in the function and fate of MDSC in the tumor and peripheral lymphoid organs, the underlying mechanisms, and their potential impact on the regulation of tumor progression.
1,339 citations
Cites background from "Epigenetic silencing of retinoblast..."
...More recently, it became apparent that those characteristics are associated with M-MDSC, whereas PMN-MDSC are nonproliferating cells that have a short half-life [51]....
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...In most types of cancer, including lung, breast, colon, renal, head and neck, pancreatic, and others, PMN-MDSC represent the major population of MDSC in mouse spleens or lymph nodes and in peripheral blood of patients with cancer [51,52]....
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TL;DR: Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases.
Abstract: The development of tumor-specific T cell tolerance is largely responsible for tumor escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal tumor models as well as in cancer patients is involved in tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter.
1,190 citations
Cites background from "Epigenetic silencing of retinoblast..."
...Whereas Rb1 M-MDSCs mainly give rise to macrophages and DCs, the vast majority of Rb1 M-MDSCs differentiate toward PMN-MDSCs (28)....
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TL;DR: This Review discusses the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.
Abstract: Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets.
1,153 citations
TL;DR: The origin and nature of myeloid-derived suppressor cells, as well as their distinctive features and biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathologic conditions ranging from cancer to obesity. These cells represent a pathologic state of activation of monocytes and relatively immature neutrophils. MDSCs are characterized by a distinct set of genomic and biochemical features, and can, on the basis of recent findings, be distinguished by specific surface molecules. The salient feature of these cells is their ability to inhibit T cell function and thus contribute to the pathogenesis of various diseases. In this Review, we discuss the origin and nature of these cells; their distinctive features; and their biological roles in cancer, infectious diseases, autoimmunity, obesity and pregnancy.
1,139 citations
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TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.
5,811 citations
TL;DR: This work considers myeloid cells as an intricately connected, complex, single system and focuses on how tumours manipulate the myeloids system to evade the host immune response.
Abstract: Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.
2,966 citations
TL;DR: The current understanding of myeloid lineage development is reviewed and the developmental pathways and cues that drive differentiation are described, which are central to the development of immunologic memory and tolerance in mice.
Abstract: Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
2,832 citations
TL;DR: The characterization and suppressive mechanisms used by myeloid-derived suppressor cells to block tumor immunity are reviewed and the mechanisms by which inflammation promotes tumor progression through the induction of MDSC are described.
Abstract: Many cancer immunotherapies developed in experimental animals have been tested in clinical trials. Although some have shown modest clinical effects, most have not been effective. Recent studies have identified myeloid-origin cells that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. "Myeloid-derived suppressor cells" (MDSC) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and experimental animals with cancer and inhibit both adaptive and innate immunity. MDSC are induced by tumor-secreted and host-secreted factors, many of which are proinflammatory molecules. The induction of MDSC by proinflammatory mediators led to the hypothesis that inflammation promotes the accumulation of MDSC that down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth. This article reviews the characterization and suppressive mechanisms used by MDSC to block tumor immunity and describes the mechanisms by which inflammation promotes tumor progression through the induction of MDSC.
1,661 citations
TL;DR: A phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells indicate that suppressive features of M DSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.
Abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G+Ly6Clow granulocytic and Ly6G−Ly6Chigh monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.
1,571 citations