The versatile plasmacytoid dendritic cell: Function, heterogeneity, and plasticity

Leylek, Rebecca; Idoyaga, Juliana

doi:10.1016/bs.ircmb.2019.10.002

Cited by 22 publications

(17 citation statements)

References 189 publications

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“…[69][70][71] Initially, it has been proposed that the engulfment of dying cancer cells by tumor-infiltrating CD8α + DCs would trigger STING signaling in the latter, culminating in the abundant secretion of type I IFN and consequent activation of autocrine and paracrine pathways supporting the crosspriming of tumor-specific CD8 + cytotoxic T lymphocytes (CTLs). [72][73][74][75][76][77][78][79] Consistent with this model, Sting1 −/mice are unable to mount efficient T cell immunity against syngeneic melanomas 57 and gliomas, 80 correlating with deficient type I IFN production. Similarly, Goldenticket mice -which harbor a single nucleotide polymorphism in Sting1 (T596A) that mimics the effects of a loss-of-function mutation -cannot establish efficient IFN-dependent immune responses against Listeria monocytogenes.…”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 53%

Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 53%

Trial watch: STING agonists in cancer therapy

et al. 2020

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“…pDCs are known for their capacity to produce IFN-I upon viral stimulation ( Reizis, 2019 ). Also, pDCs can convert into cDC-like cells by remodeling their morphology, upregulating co-stimulatory markers, increasing antigen presentation, and decreasing IFN-I production ( Leylek and Idoyaga, 2019 ). However, the chromatin dynamics underlying these 2 distinct functional outcomes are unclear.…”

Section: Resultsmentioning

confidence: 99%

“…cDCs can be further divided into cDC1 and cDC2, specialized in the activation of CD8 + and CD4 + T cells, respectively. pDCs are known for their capacity to produce large amounts of type I interferon (IFN-I) in response to viral infection followed by their conversion into cDC-like cells ( Abbas et al, 2020 ; Leylek and Idoyaga, 2019 ; Reizis, 2019 ). Advances in molecular profiling allowed the characterization of human blood DCs using single-cell RNA sequencing (scRNA-seq) ( See et al, 2017 ; Villani et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Landscape Underpinning Human Dendritic Cell Heterogeneity

et al. 2020

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SUMMARY Human dendritic cells (DCs) comprise subsets with distinct phenotypic and functional characteristics, but the transcriptional programs that dictate their identity remain elusive. Here, we analyze global chromatin accessibility profiles across resting and stimulated human DC subsets by means of the assay for transposase-accessible chromatin using sequencing (ATAC-seq). We uncover specific regions of chromatin accessibility for each subset and transcriptional regulators of DC function. By comparing plasmacytoid DC responses to IFN-I-producing and non-IFN-I-producing conditions, we identify genetic programs related to their function. Finally, by intersecting chromatin accessibility with genome-wide association studies, we recognize DC subset-specific enrichment of heritability in autoimmune diseases. Our results unravel the basis of human DC subset heterogeneity and provide a framework for their analysis in disease pathogenesis.

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“…In this setting, ELISA-based detection represents the gold standard approach, as it enables the quantitative assessment of type I IFN in a wide panel of biological specimens with superior sensitivity [184][185][186] . However, ELISAs are disadvantageous in that they cannot be harnessed to precisely identify type I IFN-producing cells within heterogeneous cell populations 187,188 . Such a disadvantage can be overcome by cytofluorometric tests based on intracellular staining with a type I IFN-specific (most often IFNB1-specific) antibody 98 .…”

Section: Monitoring the Release Of Type I Ifnsmentioning

confidence: 99%

Detection of immunogenic cell death and its relevance for cancer therapy

et al. 2020

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Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

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The versatile plasmacytoid dendritic cell: Function, heterogeneity, and plasticity

Cited by 22 publications

References 189 publications

Trial watch: STING agonists in cancer therapy

Trial watch: STING agonists in cancer therapy

Chromatin Landscape Underpinning Human Dendritic Cell Heterogeneity

Detection of immunogenic cell death and its relevance for cancer therapy

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