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Nature Reviews. Drug Discovery Nov 2022Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix... (Review)
Review
Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium.
Topics: Humans; Antineoplastic Agents; Immunotherapy; Macrophages; Neoplasms; Tumor Microenvironment
PubMed: 35974096
DOI: 10.1038/s41573-022-00520-5 -
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 -
Cell Jan 2022The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human...
The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.
Topics: Animals; Biological Evolution; Cell Nucleus; Fatty Liver; Hepatocytes; Homeostasis; Humans; Kupffer Cells; Leukocyte Common Antigens; Lipids; Liver; Lymphocytes; Macrophages; Mice, Inbred C57BL; Models, Biological; Myeloid Cells; Obesity; Proteogenomics; Proteome; Signal Transduction; Transcriptome; Mice
PubMed: 35021063
DOI: 10.1016/j.cell.2021.12.018 -
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 -
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 -
Cancer Cell Mar 2023Myeloid cells, comprised of macrophages, dendritic cells, monocytes, and granulocytes, represent a major component of the tumor microenvironment (TME) and are critically... (Review)
Review
Myeloid cells, comprised of macrophages, dendritic cells, monocytes, and granulocytes, represent a major component of the tumor microenvironment (TME) and are critically involved in regulation of tumor progression and metastasis. In recent years, single-cell omics technologies have identified multiple phenotypically distinct subpopulations. In this review, we discuss recent data and concepts suggesting that the biology of myeloid cells is largely defined by a very limited number of functional states that transcend the narrowly defined cell populations. These functional states are primarily centered around classical and pathological states of activation, with the latter state commonly defined as myeloid-derived suppressor cells. We discuss the concept that lipid peroxidation of myeloid cells represents a major mechanism that governs their pathological state of activation in the TME. Lipid peroxidation is associated with ferroptosis mediating suppressive activity of these cells and thus could be considered an attractive target for therapeutic intervention.
Topics: Humans; Myeloid Cells; Neoplasms; Macrophages; Monocytes; Myeloid-Derived Suppressor Cells; Tumor Microenvironment
PubMed: 36868224
DOI: 10.1016/j.ccell.2023.02.009 -
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 -
Annual Review of Immunology Apr 2021The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma,... (Review)
Review
The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
Topics: Animals; Brain; Central Nervous System; Humans; Macrophages; Microglia; Myeloid Cells
PubMed: 33556248
DOI: 10.1146/annurev-immunol-093019-110159 -
Cardiovascular Research Nov 2021Immune cells in atherosclerosis include T, B, natural killer (NK) and NKT cells, macrophages, monocytes, dendritic cells (DCs), neutrophils, and mast cells. Advances in... (Review)
Review
Immune cells in atherosclerosis include T, B, natural killer (NK) and NKT cells, macrophages, monocytes, dendritic cells (DCs), neutrophils, and mast cells. Advances in single-cell RNA sequencing (sRNA-Seq) have refined our understanding of immune cell subsets. Four recent studies have used scRNA-Seq of immune cells in human atherosclerotic lesions and peripheral blood mononuclear cells (PBMCs), some including cell surface phenotypes revealed by oligonucleotide-tagged antibodies, which confirmed known and identified new immune cell subsets and identified genes significantly up-regulated in PBMCs from HIV+ subjects with atherosclerosis compared to PBMCs from matched HIV+ subjects without atherosclerosis. The ability of scRNA-Seq to identify cell types is greatly augmented by adding cell surface phenotype using antibody sequencing. In this review, we summarize the latest data obtained by scRNA-Seq on plaques and human PBMCs in human subjects with atherosclerosis.
Topics: Animals; Atherosclerosis; Gene Expression Profiling; Genetic Heterogeneity; Humans; Immune System; Immunophenotyping; Leukocytes; Mice; Myeloid Cells; Phenotype; Plaque, Atherosclerotic; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 34343272
DOI: 10.1093/cvr/cvab260