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Microbiology Spectrum Nov 2016Given the dual and intrinsically contradictory roles of myeloid cells in both protective and yet also damaging effects of inflammatory and immunological processes, we... (Review)
Review
Given the dual and intrinsically contradictory roles of myeloid cells in both protective and yet also damaging effects of inflammatory and immunological processes, we suggest that it is important to consider the mechanisms and circumstances by which these cells are removed, either in the normal unchallenged state or during inflammation or disease. In this essay we address these subjects from a conceptual perspective, focusing as examples on four main myeloid cell types (neutrophils, monocytes, macrophages, and myeloid dendritic cells) and their clearance from the circulation or from naive and inflamed tissues. While the primary clearance process appears to involve endocytic uptake into macrophages, various tissue cell types can also recognize and remove dying cells, though their overall quantitative contribution is unclear. In fact, surprisingly, given the wealth of study in this area over the last 30 years, our conclusion is that we are still challenged with a substantial lack of mechanistic and regulatory understanding of when, how, and by what mechanisms migratory myeloid cells come to die and are recognized as needing to be removed, and indeed the precise processes of uptake of either the intact or fragmented cells. This reflects the extreme complexity and inherent redundancy of the clearance processes and argues for substantial investigative effort in this arena. In addition, it leads us to a sense that approaches to significant therapeutic modulation of selective myeloid clearance are still a long way off.
Topics: Animals; Autoimmune Diseases; Cell Movement; Granulomatous Disease, Chronic; Humans; Inflammation; Lupus Erythematosus, Systemic; Lymph Nodes; Lymphohistiocytosis, Hemophagocytic; Myeloid Cells
PubMed: 27837740
DOI: 10.1128/microbiolspec.MCHD-0005-2015 -
Cellular Immunology Aug 2018Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on... (Review)
Review
Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment.
Topics: Animals; Cell Proliferation; Dendritic Cells; Humans; Macrophages; Monocytes; Myeloid Cells; Neoplasms; Neutrophils; Tumor Microenvironment
PubMed: 29482836
DOI: 10.1016/j.cellimm.2018.02.008 -
Frontiers in Immunology 2020Immunotherapy with immune checkpoint inhibitors can achieve long-term tumor control in subsets of patients. However, its effect can be blunted by myeloid-induced... (Review)
Review
Immunotherapy with immune checkpoint inhibitors can achieve long-term tumor control in subsets of patients. However, its effect can be blunted by myeloid-induced resistance mechanisms. Myeloid cells are highly plastic and physiologically devoted to wound healing and to immune homeostasis maintenance. In cancer, their physiological activities can be modulated, leading to an expansion of pro-inflammatory and immunosuppressive cells, the myeloid-derived suppressor cells (MDSCs), with detrimental consequences. The involvement of MDSCs in tumor development and progression has been widely investigated and MDSC-induced immunosuppression is acknowledged as a mechanism hindering effective immune checkpoint blockade. Small non-coding RNA molecules, the microRNAs (miRs), contribute to myeloid cell regulation at different levels, comprising metabolism and function, as well as their skewing to a MDSC phenotype. miR expression can be indirectly induced by cancer-derived factors or through direct miR import via extracellular vesicles. Due to their structural stability and their presence in body fluids miRs represent promising predictive biomarkers of resistance, as we recently found by investigating plasma samples of melanoma patients undergoing immune checkpoint blockade. Dissection of the miR-driven involved mechanisms would pave the way for the identification of new druggable targets. Here, we discuss the role of these miRs in shaping myeloid resistance to immunotherapy with a special focus on immunosuppression and immune escape.
Topics: Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Immunomodulation; Immunosuppression Therapy; Immunotherapy; MicroRNAs; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms; Tumor Escape
PubMed: 32793185
DOI: 10.3389/fimmu.2020.01214 -
Cell Adhesion & Migration 2018Myeloid cell leukemia-1 (MCL-1), closely related to B-cell lymphoma 2 (BCL-2), has a well-established role in cell survival and has emerged as an important target for... (Review)
Review
Myeloid cell leukemia-1 (MCL-1), closely related to B-cell lymphoma 2 (BCL-2), has a well-established role in cell survival and has emerged as an important target for cancer therapeutics. We have demonstrated that inhibiting MCL-1 is efficacious in suppressing tumour progression in pre-clinical models of breast cancer and revealed that in addition to its role in cell survival, MCL-1 modulated cellular invasion. Utilizing a MCL-1-specific genetic antagonist, we found two possible mechanisms; firstly MCL-1 directly binds to and alters the phosphorylation of the cytoskeletal remodeling protein, Cofilin, a protein important for cytoskeletal remodeling during invasion, and secondly MCL-1 modulates the levels SRC family kinases (SFKs) and their targets. These data provide evidence that MCL-1 activities are not limited to endpoints of extracellular and intracellular signaling culminating in cell survival as previously thought, but can directly modulate the output of SRC family kinases signaling during cellular invasion. Here we review the pleotropic roles of MCL-1 and discuss the implications of this newly discovered effect on protein kinase signaling for the development of cancer therapeutics.
Topics: Animals; Breast Neoplasms; Cell Survival; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Myeloid Cells; Protein Kinases; Signal Transduction
PubMed: 29166822
DOI: 10.1080/19336918.2017.1393591 -
Clinical Science (London, England :... Oct 2023Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified...
Myeloid cells, including macrophages, play important roles as first responders to cardiac injury and stress. Epidermal growth factor receptor (EGFR) has been identified as a mediator of macrophage responsiveness to select diseases, though its impact on cardiac function or remodeling following acute ischemic injury is unknown. We aimed to define the role of myeloid cell-specific EGFR in the regulation of cardiac function and remodeling following acute myocardial infarction (MI)-induced injury. Floxed EGFR mice were bred with homozygous LysM-Cre (LMC) transgenic mice to yield myeloid-specific EGFR knockout (mKO) mice. Via echocardiography, immunohistochemistry, RNA sequencing and flow cytometry, the impact of myeloid cell-specific EGFR deletion on cardiac structure and function was assessed at baseline and following injury. Compared with LMC controls, myeloid cell-specific EGFR deletion led to an increase in cardiomyocyte hypertrophy at baseline. Bulk RNASeq analysis of isolated cardiac Cd11b+ myeloid cells revealed substantial changes in mKO cell transcripts at baseline, particularly in relation to predicted decreases in neovascularization. In response to myocardial infarction, mKO mice experienced a hastened decline in cardiac function with isolated cardiac Cd11b+ myeloid cells expressing decreased levels of the pro-reparative mediators Vegfa and Il10, which coincided with enhanced cardiac hypertrophy and decreased capillary density. Overall, loss of EGFR qualitatively alters cardiac resident macrophages that promotes a low level of basal stress and a more rapid decrease in cardiac function along with worsened repair following acute ischemic injury.
Topics: Mice; Animals; ErbB Receptors; Myeloid Cells; Macrophages; Heart; Myocardial Infarction; Mice, Transgenic; Mice, Knockout; Mice, Inbred C57BL; Ventricular Remodeling
PubMed: 37728308
DOI: 10.1042/CS20230804 -
Current Opinion in Hematology Jan 2020Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary tool in the treatment of cancer. CAR-T cells exhibit their effector functions through the recognition... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary tool in the treatment of cancer. CAR-T cells exhibit their effector functions through the recognition of their specific antigens on tumor cells and recruitment of other immune cells. However, this therapy is limited by the development of severe toxicities and modest antitumor activity in solid tumors. The host and tumor microenvironment interactions with CAR-T cells play an important role in orchestrating CAR-T-cell functions. Specifically, myeloid lineage cells and their cytokines critically influence the behavior of CAR-T cells. Here, we review the specific effects of myeloid cell interactions with CAR-T cells, their impact on CAR-T-cell response and toxicities, and potential efforts to modulate myeloid cell effects to enhance CAR-T-cell therapy efficacy and reduce toxicities.
RECENT FINDINGS
Independent studies and correlative science from clinical trials indicate that inhibitory myeloid cells and cytokines contribute to the development of CAR-T-cell-associated toxicities and impairment of their effector functions.
SUMMARY
These findings illuminate a novel way to reduce CAR-T-cell-associated toxicities and enhance their efficacy through the modulation of myeloid lineage cells and inhibitory cytokines.
Topics: Adoptive Transfer; Animals; Cytokines; Humans; Myeloid Cells; Neoplasms; Tumor Microenvironment
PubMed: 31764168
DOI: 10.1097/MOH.0000000000000559 -
Trends in Neurosciences Dec 2020The CNS accommodates a diverse myeloid immune cell compartment that maintains CNS homeostasis in the steady state while contributing to tissue injury during infectious,... (Review)
Review
The CNS accommodates a diverse myeloid immune cell compartment that maintains CNS homeostasis in the steady state while contributing to tissue injury during infectious, autoimmune, and neurodegenerative disease conditions. Autophagy and autophagy proteins play fundamental roles in myeloid cell-related immune functions. Many of these processes do not necessarily involve the canonical formation of a double-membrane structure known as the 'autophagosome' and reflect noncanonical functions of the autophagy machinery. Here, we illustrate recent insights, concepts, and outstanding questions regarding how autophagy pathways in myeloid cells contribute to brain health and disease.
Topics: Autophagy; Brain; Humans; Immunity; Myeloid Cells; Neurodegenerative Diseases
PubMed: 33010946
DOI: 10.1016/j.tins.2020.09.003 -
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 -
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 -
Frontiers in Immunology 2021
Topics: Animals; Biomarkers; Blood Platelets; Cell Communication; Disease Management; Disease Susceptibility; Humans; Immunotherapy; Killer Cells, Natural; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms; Tumor Microenvironment
PubMed: 34276709
DOI: 10.3389/fimmu.2021.718844