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Immunity May 2020The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of... (Review)
Review
The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of Differentiation 47 (CD47) protein, expressed on both healthy and cancer cells, plays a pivotal role in this balance by delivering a "don't eat me signal" upon binding to the Signal-regulatory protein alpha (SIRPα) receptor on myeloid cells. Here, we review the current understanding of the role of the CD47-SIRPα axis in physiological tissue homeostasis and as a promising therapeutic target in, among others, oncology, fibrotic diseases, atherosclerosis, and stem cell therapies. We discuss gaps in understanding and highlight where additional insight will be beneficial to allow optimal exploitation of this myeloid cell checkpoint as a target in human disease.
Topics: Animals; Antigens, Differentiation; CD47 Antigen; Homeostasis; Humans; Immunotherapy; Myeloid Cells; Neoplasms; Protein Binding; Receptors, Immunologic; Signal Transduction
PubMed: 32433947
DOI: 10.1016/j.immuni.2020.04.011 -
Nature Reviews. Cancer Apr 2023Myeloid cells are pivotal within the immunosuppressive tumour microenvironment. The accumulation of tumour-modified myeloid cells derived from monocytes or neutrophils -... (Review)
Review
Myeloid cells are pivotal within the immunosuppressive tumour microenvironment. The accumulation of tumour-modified myeloid cells derived from monocytes or neutrophils - termed 'myeloid-derived suppressor cells' - and tumour-associated macrophages is associated with poor outcome and resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Unfortunately, there has been little success in large-scale clinical trials of myeloid cell modulators, and only a few distinct strategies have been used to target suppressive myeloid cells clinically so far. Preclinical and translational studies have now elucidated specific functions for different myeloid cell subpopulations within the tumour microenvironment, revealing context-specific roles of different myeloid cell populations in disease progression and influencing response to therapy. To improve the success of myeloid cell-targeted therapies, it will be important to target tumour types and patient subsets in which myeloid cells represent the dominant driver of therapy resistance, as well as to determine the most efficacious treatment regimens and combination partners. This Review discusses what we can learn from work with the first generation of myeloid modulators and highlights recent developments in modelling context-specific roles for different myeloid cell subtypes, which can ultimately inform how to drive more successful clinical trials.
Topics: Humans; Neoplasms; Myeloid Cells; Immunotherapy; Myeloid-Derived Suppressor Cells; Neutrophils; Tumor Microenvironment
PubMed: 36747021
DOI: 10.1038/s41568-022-00546-2 -
Immunity May 2021Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has... (Review)
Review
Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.
Topics: Animals; Biomarkers; Humans; Myeloid Cells; Myeloid-Derived Suppressor Cells; Signal Transduction; T-Lymphocytes
PubMed: 33979585
DOI: 10.1016/j.immuni.2021.04.004 -
Circulation Research Apr 2022The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role...
BACKGROUND
The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis.
METHODS
We generated myeloid cell-specific PKM2 mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2Ldlr). Controls were littermate PKM2Ldlr mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high-fat Western diet for 14 weeks, starting at 8 weeks.
RESULTS
PKM2 was upregulated in macrophages of Ldlr mice fed a high-fat Western diet compared with chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2 mice associated with decreased MCP-1 (monocyte chemoattractant protein 1) levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2 mice fed the Western diet exhibited reduced expression of proinflammatory genes, including MCP-1, IL (interleukin)-1β, and IL-12. Myeloid cell-specific PKM2 mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP (LDLR-related protein)-1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP-1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr mice.
CONCLUSIONS
Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.
Topics: Animals; Aorta; Atherosclerosis; Female; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Phagocytosis; Pyruvate Kinase; Receptors, LDL
PubMed: 35400205
DOI: 10.1161/CIRCRESAHA.121.320704 -
Nature Reviews. Immunology Aug 2021Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the... (Review)
Review
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.
Topics: Autoimmune Diseases; COVID-19; Cytokines; Humans; Monocytes; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms; Neutrophils; SARS-CoV-2
PubMed: 33526920
DOI: 10.1038/s41577-020-00490-y -
Nature Reviews. Immunology Feb 2023Myeloid cells are the most abundant immune components of the tumour microenvironment, where they have a variety of functions, ranging from immunosuppressive to... (Review)
Review
Myeloid cells are the most abundant immune components of the tumour microenvironment, where they have a variety of functions, ranging from immunosuppressive to immunostimulatory roles. The myeloid cell compartment comprises many different cell types, including monocytes, macrophages, dendritic cells and granulocytes, that are highly plastic and can differentiate into diverse phenotypes depending on cues received from their microenvironment. In the past few decades, we have gained a better appreciation of the complexity of myeloid cell subsets and how they are involved in tumour progression and resistance to cancer therapies, including immunotherapy. In this Review, we highlight key features of monocyte and macrophage biology that are being explored as potential targets for cancer therapies and what aspects of myeloid cells need a deeper understanding to identify rational combinatorial strategies to improve clinical outcomes of patients with cancer. We discuss therapies that aim to modulate the functional activities of myeloid cell populations, impacting their recruitment, survival and activity in the tumour microenvironment, acting at the level of cell surface receptors, signalling pathways, epigenetic machinery and metabolic regulators. We also describe advances in the development of genetically engineered myeloid cells for cancer therapy.
Topics: Humans; Myeloid Cells; Neoplasms; Macrophages; Immunotherapy; Monocytes; Tumor Microenvironment
PubMed: 35697799
DOI: 10.1038/s41577-022-00737-w -
Science (New York, N.Y.) Jan 2019The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this...
The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets exist and what their transcriptional profiles and dynamics during CNS pathology are. Combining deep single-cell transcriptome analysis, fate mapping, in vivo imaging, clonal analysis, and transgenic mouse lines, we comprehensively characterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophage subsets undergo self-renewal, and random proliferation shifts toward clonal expansion. Last, functional studies demonstrated that endogenous CNS tissue macrophages are redundant for antigen presentation. Our results highlight myeloid cell diversity and provide insights into the brain's innate immune system.
Topics: Animals; Antigen Presentation; Brain; Central Nervous System; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Histocompatibility Antigens Class II; Homeostasis; Immunity, Innate; Inflammation; Macrophages; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; Myeloid Cells; Sequence Analysis, RNA; Single-Cell Analysis; T-Lymphocytes
PubMed: 30679343
DOI: 10.1126/science.aat7554 -
Nature Immunology Mar 2023Myeloid cells in the central nervous system (CNS), such as microglia, CNS-associated macrophages (CAMs), dendritic cells and monocytes, are vital for steady-state immune... (Review)
Review
Myeloid cells in the central nervous system (CNS), such as microglia, CNS-associated macrophages (CAMs), dendritic cells and monocytes, are vital for steady-state immune homeostasis as well as the resolution of tissue damage during brain development or disease-related pathology. The complementary usage of multimodal high-throughput and high-dimensional single-cell technologies along with recent advances in cell-fate mapping has revealed remarkable myeloid cell heterogeneity in the CNS. Despite the establishment of extensive expression profiles revealing myeloid cell multiplicity, the local anatomical conditions for the temporal- and spatial-dependent cellular engraftment are poorly understood. Here we highlight recent discoveries of the context-dependent mechanisms of myeloid cell migration and settlement into distinct subtissular structures in the CNS. These insights offer better understanding of the factors needed for compartment-specific myeloid cell recruitment, integration and residence during development and perturbation, which may lead to better treatment of CNS diseases.
Topics: Central Nervous System; Myeloid Cells; Macrophages; Microglia; Monocytes
PubMed: 36759712
DOI: 10.1038/s41590-022-01415-8 -
Annual Review of Immunology Apr 2023Myeloid cells are a significant proportion of leukocytes within tissues, comprising granulocytes, monocytes, dendritic cells, and macrophages. With the identification of... (Review)
Review
Myeloid cells are a significant proportion of leukocytes within tissues, comprising granulocytes, monocytes, dendritic cells, and macrophages. With the identification of various myeloid cells that perform separate but complementary functions during homeostasis and disease, our understanding of tissue myeloid cells has evolved significantly. Exciting findings from transcriptomics profiling and fate-mapping mouse models have facilitated the identification of their developmental origins, maturation, and tissue-specific specializations. This review highlights the current understanding of tissue myeloid cells and the contributing factors of functional heterogeneity to better comprehend the complex and dynamic immune interactions within the healthy or inflamed tissue. Specifically, we discuss the new understanding of the contributions of granulocyte-monocyte progenitor-derived phagocytes to tissue myeloid cell heterogeneity as well as the impact of niche-specific factors on monocyte and neutrophil phenotype and function. Lastly, we explore the developing paradigm of myeloid cell heterogeneity during inflammation and disease.
Topics: Mice; Humans; Animals; Monocytes; Neutrophils; Macrophages; Myeloid Cells; Inflammation; Cell Differentiation
PubMed: 37126421
DOI: 10.1146/annurev-immunol-081022-113627 -
Journal of Hematology & Oncology Aug 2022Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and... (Review)
Review
Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.
Topics: Humans; Immunosuppression Therapy; Immunotherapy; Myeloid Cells; Neoplasms; Tumor Microenvironment
PubMed: 36031601
DOI: 10.1186/s13045-022-01335-y