The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting

Mérad, Miriam; Sathe, Priyanka; Helft, Julie; Miller, Jennifer C.; Mortha, Arthur

doi:10.1146/annurev-immunol-020711-074950

Cited by 1,942 publications

(2,250 citation statements)

References 298 publications

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“…36 Thus, it will be interesting to dissect the differentiation fate and functionality of the Ly6C hi monocytes that were recruited by supernatants of irradiated tumor cells in our model in greater detail, for instance if they – in the course of differentiation – give rise to the Ly6C lo monocytic population which appeared in the air pouches, or if these cells rather are of tissue-resident origin. 52 …”

Section: Discussionmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

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The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 × 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses – at least in models of triple-negative breast cancer.

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Section: Discussionmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

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“…In the blood, human DC include lineage-negative (LIN-) HLA-DR+CD14-CD11c-CD123+ plasmacytoid DC and LIN-HLA-DR+CD14-CD11c+ conventional DC subsets, of which the latter can be subdivided into four different DC subsets (DC1 to DC4) based on the additional markers CLEC9A, CD141, CD1c, CD16, CD36, CD32b and CD163. 23 , 28 Blood analysis of six EOC patients and four healthy donors revealed that the HLA-DR+CD14-CD11c+ DC subset was mainly composed of CD141+CLEC9A+ DC1, CD1c+CD32b+ DC2, CD1 c+CD32b-CD36+CD163+ DC3 and CD1c-CD16+ DC4 subsets ( Suppl. Fig.…”

Section: Resultsmentioning

confidence: 99%

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

et al. 2018

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Epithelial ovarian cancer (EOC) may cause abnormal blood levels of leukocytes. This paraneoplastic manifestation is associated with a worse response to therapy and shorter survival. To understand the complexity and nature of these leukocytes, we dissected the different populations of myeloid cells and analyzed their relation to clinical outcome. Therefore, baseline blood samples of 36 EOC patients treated either with carboplatin/doxorubucin or with gemcitabine were analyzed for different subsets of monocytes/macrophages, myeloid derived suppressor cells (MDSC) and dendritic cells (DC) using multiparameter flow cytometry as well as functional assays for myeloid cell mediated suppression of antigen-specific T cell reactivity. Healthy donor blood served as control. EOC patients displayed an increase in monocytes/macrophages, monocytic MDSC (mMDSC) and CD33-CD11b+CD14-CD15- double-negative MDSC (CD33- dnMDSC) and a decrease in the frequency of DC, across all EOC subtypes. A low frequency of DC and high frequencies of monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were associated with poor overall survival. Patient's monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were shown to suppress T cell reactivity in vitro. The mMDSC and DC frequencies were not altered upon treatment. Importantly, the mMDSC to DC ratio was the strongest independent, highly sensitive and specific, predictive factor for survival. This was irrespective of the type of chemotherapy or disease stage and outperformed classical parameters as WHO status or time from last chemotherapy. Thus, the baseline blood mMDSC to DC ratio is a robust, independent and easy to analyze predictive factor for EOC survival, and may assist patient selection for immunotherapy.

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“…1). The great majority of ‘professional’ DC in vivo derive from bone marrow pre‐DC 1. In this regard, studies addressing the effects of VD3 on murine DC have mostly cultured whole bone marrow with GM‐CSF or GM‐SCF + IL‐4 to generate CD11c + cells (GM‐CSF‐DC).…”

Section: Vd3 and DC Precursor (Pre‐dc) Derived Dc In The Mousementioning

confidence: 99%

“…CDP‐derived precursors exhibit early specialization to gut‐tropic mucosal DC precursors (pre‐μDC), regulated by retinoic acid (RA)6, 49 and classical DC precursors (pre‐cDC), and within the latter into cDC1 or cDC2 lineages in the bone marrow 80. Pre‐cDC and pre‐μDC then circulate through blood and home to tissues where they complete their differentiation under tissue‐specific influences 1, 6, 38, 49. The cMoP differentiate to human CD14 + /mouse Ly6C + monocytes and circulate through blood.…”

Section: Vd3 and DC Precursor (Pre‐dc) Derived Dc In The Mousementioning

confidence: 99%

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Vitamin D immunoregulation through dendritic cells

2016

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SummaryVitamin D (VD3) has been linked to immunological processes, and its supplementation may have a role in treatment or prevention of diseases with underlying autoimmune or pro‐inflammatory states. As initiators of the immune responses, dendritic cells (DC) are a potential target of VD3 to dampen autoimmunity and inflammation, but the role of DC in VD3‐mediated immunomodulation in vivo is not understood. In addition to being targets of VD3, DC can provide a local source of bioactive VD3 for regulation of T‐cell responses. Here we review existing studies that describe the tolerogenic potential of VD3 on DC, and discuss them in the context of current understanding of DC development and function. We speculate on mechanisms that might account for the potent but poorly understood tolerogenic activities of VD3 and the role of DC as both targets and sources of this hormone.

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The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting

Cited by 1,942 publications

References 298 publications

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

Vitamin D immunoregulation through dendritic cells

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