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International Review of Cell and... 2023Myeloid-derived suppressor cells (MDSCs), which originated from hematopoietic stem cells, are heterogeneous population of cells that have different differentiation... (Review)
Review
Myeloid-derived suppressor cells (MDSCs), which originated from hematopoietic stem cells, are heterogeneous population of cells that have different differentiation patterns and widely presented in tumor microenvironment. For tumor research, myeloid suppressor cells have received extensive attention since their discovery due to their specific immunosuppressive properties, and the mechanisms of immunosuppression and therapeutic approaches for MDSCs have been investigated in a variety of different types of malignancies. To improve the efficacy of treatment for head and neck squamous cell carcinoma (HNSCC), a disease with a high occurrence, immunotherapy has gradually emerged in after traditional surgery and subsequent radiotherapy and chemotherapy, and has made some progress. In this review, we introduced the mechanisms on the development, differentiation, and elimination of MDSCs and provided a detailed overview of the mechanisms behind the immunosuppressive properties of MDSCs. We summarized the recent researches on MDSCs in HNSCC, especially for targeting-MDSCs therapy and combination with other types of therapy such as immune checkpoint blockade (ICB). Furthermore, we looked at drug delivery patterns and collected the current diverse drug delivery systems for the improvement that contributed to therapy against MDSCs in HNSCC. Most importantly, we made possible outlooks for the future research priorities, which provide a basis for further study on the clinical significance and therapeutic value of MDSCs in HNSCC.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Myeloid-Derived Suppressor Cells; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Myeloid Cells; Tumor Microenvironment
PubMed: 36967154
DOI: 10.1016/bs.ircmb.2022.11.002 -
Journal of Thrombosis and Haemostasis :... Feb 2024Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.
BACKGROUND
Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.
OBJECTIVES
We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.
METHODS
We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.
RESULTS
Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice.
CONCLUSION
Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.
Topics: Animals; Mice; Protein C; Endothelial Protein C Receptor; Myeloid Cells; Inflammation; Thrombophilia; Glycolysis; Mice, Inbred C57BL
PubMed: 37865288
DOI: 10.1016/j.jtha.2023.10.006 -
Cells Aug 2022Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage... (Review)
Review
Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of leads to massive accumulation of CD11bGr1 immature myeloid cells (IMCs), particularly the CD11bLy6CLy6G polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b Ly6GLy6C monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.
Topics: Animals; Humans; Interferon Regulatory Factors; Mice; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms
PubMed: 36078039
DOI: 10.3390/cells11172630 -
Frontiers in Immunology 2023The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the... (Review)
Review
The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an "integrated defense system" that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.
Topics: Humans; Nociceptors; Sensory Receptor Cells; Pain; Peripheral Nervous System; Myeloid Cells
PubMed: 37006298
DOI: 10.3389/fimmu.2023.1127571 -
Seminars in Immunology Jun 2021The dysregulation of myeloid cell responses is increasingly demonstrated to be a major mechanism of pathogenesis for COVID-19. The pathological cellular and cytokine... (Review)
Review
The dysregulation of myeloid cell responses is increasingly demonstrated to be a major mechanism of pathogenesis for COVID-19. The pathological cellular and cytokine signatures associated with this disease point to a critical role of a hyperactivated innate immune response in driving pathology. Unique immunopathological features of COVID-19 include myeloid-cell dominant inflammation and cytokine release syndrome (CRS) alongside lymphopenia and acute respiratory distress syndrome (ARDS), all of which correlate with severe disease. Studies suggest a range of causes mediating myeloid hyperactivation, such as aberrant innate sensing, asynchronized immune cellular responses, as well as direct viral protein/host interactions. These include the recent identification of new myeloid cell receptors that bind SARS-CoV-2, which drive myeloid cell hyperinflammatory responses independently of lung epithelial cell infection via the canonical receptor, angiotensin-converting enzyme 2 (ACE2). The spectrum and nature of myeloid cell dysregulation in COVID-19 also differs from, at least to some extent, what is observed in other infectious diseases involving myeloid cell activation. While much of the therapeutic effort has focused on preventative measures with vaccines or neutralizing antibodies that block viral infection, recent clinical trials have also targeted myeloid cells and the associated cytokines as a means to resolve CRS and severe disease, with promising but thus far modest effects. In this review, we critically examine potential mechanisms driving myeloid cell dysregulation, leading to immunopathology and severe disease, and discuss potential therapeutic strategies targeting myeloid cells as a new paradigm for COVID-19 treatment.
Topics: Humans; Immunity, Innate; Myeloid Cells; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34823995
DOI: 10.1016/j.smim.2021.101524 -
Acta Neuropathologica Communications Jul 2023Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates...
Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.
Topics: Animals; Mice; Agammaglobulinaemia Tyrosine Kinase; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Mice, Biozzi; Myeloid Cells
PubMed: 37438842
DOI: 10.1186/s40478-023-01614-w -
Theranostics 2023: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor...
: Hepatocellular carcinoma (HCC) is primarily characterized by a high incidence of vascular invasion. However, the specific mechanism underlying portal vein tumor thrombus (PVTT) in HCC remains unclear. As a consequence of myeloid cell developmental arrest, CD71 erythroid progenitor cells (EPCs) and myeloid-derived suppressor cells play important roles in HCC; however, their roles in PVTT remain unclear. The role of CD71 EPCs in the HCC tumor microenvironment (TME) was evaluated via morphological, RNA-sequencing, enzyme-linked immunosorbent assay, and flow cytometric analyses. Co-culture techniques were employed to assess the CD45 EPCs and their vascular compromising effect. Additionally, the PVTT-promoting function of CD45 EPCs was explored in a murine model. The CD45EPCs in HCC tissues exhibited increased myeloid cell features, including morphology, surface markers, transforming growth factor (TGF)-β generation, and gene expression, compared with those in circulation. Hence, a large proportion of CD45EPCs, particularly those in TMEs, comprise erythroid-transdifferentiated myeloid cells (EDMCs). Additionally, the expression of C-C chemokine receptor type 2 (CCR2) mRNA was upregulated in CD45EPCs within the TME. Tumor macrophages from HCC tissues induced substantial migration of CD45EPCs in a dose-dependent manner. Meanwhile, results from immunofluorescence analyses revealed that these two cell types are positively associated in the TME and circulation. That is, EDMCs are chemoattracted by HCC macrophages mainly via CCR2 from CD45 EPCs in the circulation. Additionally, the expressions of FX, FVII, FGB, C4b, CFB, and CFH were elevated in CD45EPCs within the TME compared with those in the spleen. The CD45EPCs from the HCC TME promoted vessel endothelial cell migration and compromised tube formation through TGF-β and FGB, respectively. Additionally, CD45EPCs from the TME induced HCC cell migration. HCC macrophage-induced CD45EPCs to exhibit higher levels of FX, FVII, FGB, and TGF-β. Meanwhile, upregulation of CCAAT/enhancer binding protein beta expression induced FGB and TGF-β generation in CD45EPCs in the TME. WTAP, a major RNA mA writer, stabilized and mRNA and enhanced their nuclear export in CD45EPCs from the TME. CD45EPCs from the TME were positively associated with PVTT and poor prognosis. Splenectomy reduced the level of CD45EPCs in the circulation and TME, as well as the incidence of microvascular invasion. The incidence of microvascular invasion increased following the transfer of HCC tissue CD45EPCs to splenectomized HCC-bearing mice. The CD45EPCs enriched in the HCC microenvironment are EDMCs, which are induced by HCC macrophages to migrate from the circulation to the TME. Subsequently, EDMCs promote PVTT by compromising the blood vessel endothelium, aggravating coagulation, and promoting HCC cell migration.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Portal Vein; Liver Neoplasms; Myeloid Cells; Thrombosis; Tumor Microenvironment
PubMed: 37649603
DOI: 10.7150/thno.82907 -
Advanced Drug Delivery Reviews Jun 2023In the presence of tissue inflammation, injury, or cancer, myeloid cells are recruited to disease regions through a multi-step process involving myelopoiesis,... (Review)
Review
In the presence of tissue inflammation, injury, or cancer, myeloid cells are recruited to disease regions through a multi-step process involving myelopoiesis, chemotaxis, cell migration, and diapedesis. As an emerging drug delivery approach, cell-mediated drug delivery takes advantage of the cell recruitment process to enhance the active transport of therapeutic cargo to disease regions. In the past few decades, a variety of nano-engineering methods have emerged to enhance interactions of nanoparticles with cells of interest, which can be adapted for cell-mediated drug delivery. Moreover, the drug delivery field can benefit from the recent clinical success of cell-based therapies, which created cell-engineering methods to engineer circulating leukocytes as 'living drug delivery vehicles' to target diseased tissues. In this review, we first provide an overview of myeloid cell recruitment and discuss how various factors within this process may affect cell-mediated delivery. In the second part of this review article, we summarize the status quo of nano-engineering and cell-engineering approaches and discuss how these engineering approaches can be adapted for cell-mediated delivery. Finally, we discuss future directions of this field, pointing out key challenges in the clinical translation of cell-mediated drug delivery.
Topics: Humans; Drug Carriers; Nanomedicine; Drug Delivery Systems; Nanoparticles; Myeloid Cells; Cell- and Tissue-Based Therapy
PubMed: 37068659
DOI: 10.1016/j.addr.2023.114827 -
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 -
Frontiers in Immunology 2024
Topics: Humans; Cellular Reprogramming; Myeloid Cells; Animals; Signal Transduction
PubMed: 38745655
DOI: 10.3389/fimmu.2024.1414482