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Analysis of human classical and non-classical monocytes compared to their dendritic cell counterpart.

ABSTRACT: Peripheral blood monocytes are the starting material utilized in conventional dendritic cell (DC) vaccination for the treatment of a broad range of malignancies. While the use of cytokines and growth factors to polarize monocyte-derived DC to distinct phenotypes is well-established, little is known about the contributions of distinct human monocyte subsets to monocyte-derived DC function and patient responses to vaccination. To investigate the status of monocyte subsets in cancer patients and following culture into DC, we isolated classical (C-Mo), intermediate (I-Mo), and non-classical (NC-Mo) from the peripheral blood of renal cell carcinoma (RCC) patients prior to DC vaccination (NCT00085436) and from anonymous healthy donors. Patients treated with DC vaccination who were long term survivors (>100 months survival) had a unique monocyte signature with a two-fold higher percentage of NC-Mo in pretreatment peripheral blood compared to other RCC patients. RCC patient monocytes from each subset were transcriptionally distinct from healthy donor monocytes. Further transcriptional analysis determined that each monocyte subset was characterized by a discrete gene expression profile before and after DC maturation. Phenotypic analysis showed that DC derived from NC-Mo expressed higher levels of CD80, CD83, CD86, HLA-DR, and CD40 compared to DC originating from C-Mo and secreted increased amounts of IL-12p70 following CD40L stimulation. Collectively, these findings establish that DC derived from NC-Mo are potent antigen presenting cells and provide the foundation for future vaccination strategies that enrich NC-Mo prior to DC maturation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106840 | GEO | 2019/11/15

REPOSITORIES: GEO

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Analysis of classical monocytes from healthy donors, pretreatment RCC patients, and RCC long term survivors.

Project description:Peripheral blood monocytes are the starting material utilized in conventional dendritic cell (DC) vaccination for the treatment of a broad range of malignancies. While the use of cytokines and growth factors to polarize monocyte-derived DC to distinct phenotypes is well-established, little is known about the contributions of distinct human monocyte subsets to monocyte-derived DC function and patient responses to vaccination. To investigate the status of monocyte subsets in cancer patients and following culture into DC, we isolated classical (C-Mo), intermediate (I-Mo), and non-classical (NC-Mo) from the peripheral blood of renal cell carcinoma (RCC) patients prior to DC vaccination (NCT00085436) and from anonymous healthy donors. Patients treated with DC vaccination who were long term survivors (>100 months survival) had a unique monocyte signature with a two-fold higher percentage of NC-Mo in pretreatment peripheral blood compared to other RCC patients. RCC patient monocytes from each subset were transcriptionally distinct from healthy donor monocytes. Further transcriptional analysis determined that each monocyte subset was characterized by a discrete gene expression profile before and after DC maturation. Phenotypic analysis showed that DC derived from NC-Mo expressed higher levels of CD80, CD83, CD86, HLA-DR, and CD40 compared to DC originating from C-Mo and secreted increased amounts of IL-12p70 following CD40L stimulation. Collectively, these findings establish that DC derived from NC-Mo are potent antigen presenting cells and provide the foundation for future vaccination strategies that enrich NC-Mo prior to DC maturation.

2019-11-15 | GSE106771 | GEO

Analysis of monocyte subsets from pretreatment RCC patients compared to healthy donors.

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The slan antigen identifies the prototypical non-classical CD16+-monocytes in human blood [Bulk RNA-seq]

Project description:Peripheral monocytes in humans are conventionally divided into classical (CL, CD14++CD16−), intermediate (INT, CD14++CD16+) and non-classical (NC, CD14dim/−CD16++) cells, based on their expression levels of CD14 and CD16. A major fraction of the NC-monocytes has been shown to express the 6-sulfo LacNAc (slan) antigen, but whether these slan+/NC-monocytes represent the prototypical non-classical monocytes or whether they are simply a sub-fraction with identical features as the remainder of NC monocytes is still unclear. Therefore, we analysed transcriptome, proteome, cell surface markers and production of discrete cytokines by peripheral slan+/NC- and slan−/NC-monocytes, in comparison to total NC-, CL- and INT- monocytes. By bulk RNA-seq and proteomic analysis, we found that slan+/NC-monocytes express higher levels of genes and proteins specific of NC-monocytes than slan−/NC-monocytes do. Unsupervised clustering of scRNA-seq data generated one cluster of NC- and one of INT-monocytes, where all slan+/NC-monocytes were allocated to the NC-monocyte cluster, while slan−/NC-monocytes were found, in part (13.38 %), within the INT-monocyte cluster. In addition, total NC- and slan−/NC-monocytes, but not slan+/NC-monocytes, were found by both bulk RNA-seq and scRNA-seq to contain a small percentage of natural killer cells. Altogether, in addition to comparatively characterize total NC-, slan−/NC- and slan+/NC-monocyte transcriptomes and proteomes, our data prove that slan+/NC-, but not slan−/NC-, monocytes are more representative of prototypical NC-monocytes.

2023-10-19 | GSE242301 | GEO

The slan antigen identifies the prototypical non-classical CD16+-monocytes in human blood [scRNA-seq]

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Innate cells and STAT1-dependent signals orchestrate vaccine-induced protection against invasive Cryptococcus infection

Project description:Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2+ monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2+ cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c+ cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection.

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NR4A3 plays a pivotal role in the differentiation of monocyte-derived dendritic cells

Project description:The molecular requirements that guide the differentiation of monocytes into macrophages or monocyte-derived dendritic cells (Mo-DCs) are poorly understood. Here, we demonstrate that the nuclear orphan receptor NR4A3 guides monocyte fate and is essential for Mo-DC differentiation. Nr4a3-/- mice are impaired in the in vivo generation of DC-SIGN+ Mo-DCs following LPS stimulation and, as such, are defective at priming a CD8+ T cell response to gram negative bacteria. We also demonstrate that NR4A3 is an essential downstream effector of IRF4 during in vitro differentiation of Mo-DCs with GM-CSF and IL-4 and that, in absence of NR4A3, monocytes are diverted to macrophages. Our transcriptomic analysis of the genes regulated by NR4A3 reveals that the acquisition of the Mo-DC differentiation program is intertwined with the acquisition of a migratory signature. Furthermore, NR4A3 is critical for steady-state migration of non-lymphoid tissue conventional DCs to lymph nodes. Altogether, our results highlight a unique role for NR4A3 in Mo-DC differentiation and in the acquisition of migratory properties.

2019-06-25 | GSE99837 | GEO

Genomic expression analysis of human monocyte-derived DCs and monocytes

Project description:To identify the functional non-coding RNAs in human DC development, we explored the gene expression profiles during DC development from peripheral monocytes. Using RNA-seq, we identified many annotated lncRNAs with markedly altered expressions during human DC differentiation and maturation. RNA samples from human peripheral blood monocytes and monocyte-derived DCs were collected. RNAs from 3 donors were pooled together to form monocyte sample or DC sample and then these two samples were subjected to RNA-seq and analysis.

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Murine GMP- and MDP-derived classical monocytes have distinct functions and fates [dataset 2]

Project description:Monocytes are short-lived myeloid immune cells that arise from adult hematopoiesis and circulate for a short time in the blood. They comprise two main subsets, in mice defined as classical Ly6Chigh and non-classical Ly6Clow monocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM in the BM and blood. Functional characterization, including fate definition following adoptive cell transfer, established that GMP-Mo and MDP-Mo could equal rise to homeostatic CM progeny, such as NCM in blood and gut macrophages, but differentially seeded selected other tissues. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, thus linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide comprehensive evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge. Our findings are indicative of impact of monocyte ontogeny on in situ differentiation.

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Analysis of blood myelomonocytic cells from RCC patients

Project description:Myelomonocytic cells (i.e., monocytes or macrophages) play a key role in tumor progression as revealed by numerous mice tumor model studies. However, their contribution in human tumor progression is not well-studied. Using Renal Cell Carcinoma (RCC) as a model for human cancer, we performed a transcriptomal profiling of blood monocytes from RCC patients to investigate the contribution of these cells in cancer progression. As compared to monocytes from healthy donors (Mo), transcriptome analysis of monocytes from RCC patients (RCC-Mo) showed a distinct gene expression signature consisting of cytokines, chemokines and various inflammation-related genes. Validation of these genes by qPCR as well as other functional assays indicated RCC-Mo possess an inflammatory and tumor promoting phenotype.

2014-10-30 | GSE38424 | GEO

Microarray expression data from WT and IRF4 KO Sirp-a+ DCs

Project description:Cross-presentation of cell-associated antigens is carried out by classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs), but whether a similar or distinct program exists for this process is unknown. In examining this issue, we discovered that only Ly-6ChiTremL4– monocytes, but not Ly-6ChiTremL4+ monocytes, can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4. However, Ly-6ChiTremL4+ monocytes were committed to Nur77-dependent development of Ly-6CloTremL4+ monocytes. Further, differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46+ Mo-DCs that cross-presented as efficiently as CD24+ cDCs, which was accompanied by increased Batf3 and Irf4 expression. Unlike cDCs, Mo-DCs required only IRF4, and not Batf3, for cross-presentation. Further, Irf4–/– monocytes failed to develop into Zbtb46+ Mo-DCs, and instead developed into macrophages. Thus, cDCs and Mo-DCs use distinct transcriptional programs for cross-presentation that may drive different antigen-processing pathways. These differences may influence development of therapeutic DC vaccines based on Mo-DCs.

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