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Frontiers in Immunology 2023Dendritic cells (DCs) are sentinel immune cells that form a critical bridge linking the innate and adaptive immune systems. Extensive research addressing the cellular... (Review)
Review
Dendritic cells (DCs) are sentinel immune cells that form a critical bridge linking the innate and adaptive immune systems. Extensive research addressing the cellular origin and heterogeneity of the DC network has revealed the essential role played by the spatiotemporal activity of key transcription factors. In response to environmental signals DC mature but it is only following the sensing of environmental signals that DC can induce an antigen specific T cell response. Thus, whilst the coordinate action of transcription factors governs DC differentiation, sensing of environmental signals by DC is instrumental in shaping their functional properties. In this review, we provide an overview that focuses on recent advances in understanding the transcriptional networks that regulate the development of the reported DC subsets, shedding light on the function of different DC subsets. Specifically, we discuss the emerging knowledge on the heterogeneity of cDC2s, the ontogeny of pDCs, and the newly described DC subset, DC3. Additionally, we examine critical transcription factors such as IRF8, PU.1, and E2-2 and their regulatory mechanisms and downstream targets. We highlight the complex interplay between these transcription factors, which shape the DC transcriptome and influence their function in response to environmental stimuli. The information presented in this review provides essential insights into the regulation of DC development and function, which might have implications for developing novel therapeutic strategies for immune-related diseases.
Topics: Gene Expression Regulation; Cell Differentiation; Transcriptome; Dendritic Cells
PubMed: 37520521
DOI: 10.3389/fimmu.2023.1182553 -
Cells Oct 2023Non-small-cell lung cancer (NSCLC) remains one of the leading causes of death worldwide. While NSCLCs possess antigens that can potentially elicit T cell responses,... (Review)
Review
Non-small-cell lung cancer (NSCLC) remains one of the leading causes of death worldwide. While NSCLCs possess antigens that can potentially elicit T cell responses, defective tumor antigen presentation and T cell activation hinder host anti-tumor immune responses. The NSCLC tumor microenvironment (TME) is composed of cellular and soluble mediators that can promote or combat tumor growth. The composition of the TME plays a critical role in promoting tumorigenesis and dictating anti-tumor immune responses to immunotherapy. Dendritic cells (DCs) are critical immune cells that activate anti-tumor T cell responses and sustain effector responses. DC vaccination is a promising cellular immunotherapy that has the potential to facilitate anti-tumor immune responses and transform the composition of the NSCLC TME via tumor antigen presentation and cell-cell communication. Here, we will review the features of the NSCLC TME with an emphasis on the immune cell phenotypes that directly interact with DCs. Additionally, we will summarize the major preclinical and clinical approaches for DC vaccine generation and examine how effective DC vaccination can transform the NSCLC TME toward a state of sustained anti-tumor immune signaling.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Tumor Microenvironment; Antigens, Neoplasm; Vaccination; Dendritic Cells
PubMed: 37830618
DOI: 10.3390/cells12192404 -
Proceedings of the National Academy of... Aug 2023Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has...
Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has remained unclear. We here show that T cell-specific CD47-deficient () mice have a markedly reduced number of T cells in peripheral tissues. Direct interaction of CD47-deficient T cells with cDCs resulted in activation of the latter cells, which in turn induced necroptosis of the former cells. The deficiency and cell death of T cells in mice required expression of its receptor signal regulatory protein α on cDCs. The development of CD4 T helper cell-dependent contact hypersensitivity and inhibition of tumor growth by cytotoxic CD8 T cells were both markedly impaired in mice. CD47 on T cells thus likely prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function.
Topics: Animals; Mice; CD47 Antigen; CD8-Positive T-Lymphocytes; Cell Survival; Dendritic Cells; Necroptosis; Receptors, Immunologic
PubMed: 37549290
DOI: 10.1073/pnas.2304943120 -
Cells Aug 2023In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However,... (Review)
Review
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
Topics: Humans; Biocompatible Materials; Dendritic Cells; Drug-Related Side Effects and Adverse Reactions; Extracellular Vesicles; Immunogenic Cell Death
PubMed: 37681880
DOI: 10.3390/cells12172147 -
Nature Communications Nov 2023Efficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we...
Efficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we analyze the transcriptomic and immune-metabolic profiles of Dendritic Cells (DCs) from 35 subjects enrolled in a trial of DC vaccines in late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker of DC function and patient overall survival (OS). We demonstrate multiple immune and metabolic gene expression pathway alterations, a functional decrease in OCR/OXPHOS and increase in ECAR/glycolysis in patient vaccines. To dissect molecular mechanisms, we utilize single cell SCENITH functional profiling and show patient clinical outcomes (OS) correlate with DC metabolic profile, and that metabolism is linked to immune phenotype. With single cell metabolic regulome profiling, we show that MCT1 (monocarboxylate transporter-1), a lactate transporter, is increased in patient DCs, as is glucose uptake and lactate secretion. Importantly, pre-vaccination circulating myeloid cells in patients used as precursors for DC vaccine generation are significantly skewed metabolically as are several DC subsets. Together, we demonstrate that the metabolic profile of DC is tightly associated with the immunostimulatory potential of DC vaccines from cancer patients. We link phenotypic and functional metabolic changes to immune signatures that correspond to suppressed DC differentiation.
Topics: Humans; Melanoma; Metabolomics; Research Personnel; Cancer Vaccines; Dendritic Cells
PubMed: 37938561
DOI: 10.1038/s41467-023-42881-4 -
Frontiers in Immunology 2023Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional... (Review)
Review
Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional therapies (surgery combined with radiochemotherapy), resulting in poor prognosis. Meanwhile, due to its "cold tumor" phenotype, GBM fails to respond to multiple immunotherapies. As its capacity to prime T cell response, dendritic cells (DCs) are essential to anti-tumor immunity. In recent years, as a therapeutic method, dendritic cell vaccine (DCV) has been immensely developed. However, there have long been obstacles that limit the use of DCV yet to be tackled. As is shown in the following review, the role of DCs in anti-tumor immunity and the inhibitory effects of tumor microenvironment (TME) on DCs are described, the previous clinical trials of DCV in the treatment of GBM are summarized, and the challenges and possible development directions of DCV are analyzed.
Topics: Humans; Glioma; Glioblastoma; Brain Neoplasms; Dendritic Cells; Cancer Vaccines; Tumor Microenvironment
PubMed: 37781367
DOI: 10.3389/fimmu.2023.1259562 -
Journal of Leukocyte Biology Jul 2023Allergic asthma is a chronic inflammatory disease characterized by Th2, conventional dendritic cell, and B-cell activation. In addition to excessive inflammation, asthma...
Allergic asthma is a chronic inflammatory disease characterized by Th2, conventional dendritic cell, and B-cell activation. In addition to excessive inflammation, asthma pathogenesis includes dysregulation of anti-inflammatory pathways, such as the CD200/CD200R pathway. Thus, we investigated whether a CD200R agonist, CD200Fc, could disrupt the inflammatory cascade in chronic allergic asthma pathogenesis using a mice model of experimental asthma. Mice were exposed to house dust mites for 5 wk, and CD200Fc treatment was initiated after chronic inflammation was established (starting on week 4). We demonstrate that chronic house dust mite exposure altered CD200 and CD200R expression on lung immune cell populations, including upregulation of CD200 on alveolar macrophages and reduced expression of CD200 on conventional dendritic cells. CD200Fc treatment does not change bronchoalveolar cellular infiltration, but it attenuates B-cell activation and skews the circulating immunoglobulin profile toward IgG2a. This is accompanied by reduced activation of conventional dendritic cells, including lower expression of CD40, especially on conventional dendritic cell subset 2 CD200R+. Furthermore, we confirm that CD200Fc can directly modulate conventional dendritic cell activation in vitro using bone marrow-derived dendritic cells. Thus, the CD200/CD200R pathway is dysregulated during chronic asthma pathogenesis, and the CD200R agonist modulates B-cell and dendritic cell activation but, in our chronic model, is not sufficient to alter inflammation measured in bronchoalveolar lavage.
Topics: Mice; Animals; Pyroglyphidae; Asthma; Inflammation; Allergens; Dendritic Cells
PubMed: 37032534
DOI: 10.1093/jleuko/qiad042 -
Cytometry. Part a : the Journal of the... Jun 2024We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with...
We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with the goal of maximizing the amount of information that can be collected using currently available flow cytometry platforms. We established and tested this panel using peripheral blood mononuclear cells (PBMCs), but included CD45 to enable its future use for the analysis of human tissue samples. The panel contains lineage markers for all major immune cell subsets, and an extensive set of phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment. We outline the biological insight that can be gained from the simultaneous measurement of such a large number of proteins and propose that this approach provides a unique opportunity for the comprehensive exploration of the immune status in human samples with a limited number of cells. Of note, we tested the panel to be compatible with cell sorting for further downstream applications. Furthermore, to facilitate the wide-spread implementation of such a panel across different cohorts and samples, we established a trimmed-down 45-color version which can be used with different spectral cytometry platforms. Finally, to generate this panel, we utilized not only existing panel design guidelines, but also developed new metrics to systematically identify the optimal combination of 50 fluorochromes and evaluate fluorochrome-specific resolution in the context of a 50-color unmixing matrix.
Topics: Humans; Dendritic Cells; Flow Cytometry; Immunophenotyping; T-Lymphocytes; Leukocytes, Mononuclear; Immune System; Phenotype; Biomarkers
PubMed: 38634730
DOI: 10.1002/cyto.a.24841 -
Italian Journal of Dermatology and... Aug 2023Despite the amazing advances produced in our understanding of the pathogenesis of psoriasis, which have led to a therapeutic revolution, our knowledge of the mechanisms... (Review)
Review
Despite the amazing advances produced in our understanding of the pathogenesis of psoriasis, which have led to a therapeutic revolution, our knowledge of the mechanisms of relapse and elicitation of lesions is just starting to unravel. This narrative review tours the different cell types and mechanisms involved in the priming, maintenance, and relapse of psoriasis vulgaris. Our discussion includes dendritic cells, T cells, tissue resident memory cells and mast cells, with a foray into the epigenetic mechanisms of inflammatory memory in keratinocytes. Increasing knowledge is providing a glimpse of a potential therapeutic window of opportunity in psoriasis, providing long term remission and eventual modification of the natural history of the disease.
Topics: Humans; Psoriasis; Recurrence; Keratinocytes; T-Lymphocytes; Dendritic Cells
PubMed: 37404193
DOI: 10.23736/S2784-8671.23.07583-7 -
Immunology Letters Sep 2023Toll-like receptors (TLR)s are homo- or heterodimeric proteins, whose structure and function were widely described in the antigen presenting cells (APC), such as... (Review)
Review
Toll-like receptors (TLR)s are homo- or heterodimeric proteins, whose structure and function were widely described in the antigen presenting cells (APC), such as Dendritic cells (DC). Recently, the expression and the role of TLRs in fighting against pathogens, was described also in NK cells. Their activation and functional properties can be directly and indirectly modulated by agonists for TLRs. In particular CD56 NK cells subset, that is the most abundant NK cell subset in tissues and tumor microenvironment (TME), was mostly activated in terms of pro-inflammatory cytokine production, proliferation and cytotoxicity, by agonists specific for endosomal TLR8. The interplay between DC and NK, that depends on both cell-to-cell contact and soluble factors such as cytokines, promote both DC maturation and NK cell activation. Based on this concept, a TLR based immunotherapy aimed to activate NK-DC axis, may modulate TME by inducing a pro-inflammatory phenotype, thus improving DC ability to present tumor-associated antigens to T cells, and NK cell cytotoxicity against tumor cells. In this mini-review, we report data of recent literature about TLRs on human NK cells and their application as adjuvant in cancer vaccines or in combined tumor immunotherapy.
Topics: Humans; Toll-Like Receptor 8; Toll-Like Receptors; Killer Cells, Natural; Immunotherapy; Neoplasms; Dendritic Cells; Toll-Like Receptor 7; Tumor Microenvironment
PubMed: 37451320
DOI: 10.1016/j.imlet.2023.07.003