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Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted therapies in colon cancer

ABSTRACT: Single cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application towards dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a conventional dendritic cell population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146771 | GEO | 2020/04/18

REPOSITORIES: GEO

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Single-cell RNA-sequencing of immune cells in (1) mouse Renca model treated with anti-CSF1R and (2) mouse MC38 model treated with anti-CD40

Project description:Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application towards dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune cells in mouse tumors and identified specific macrophage and conventional dendritic cell (cDC) subsets that are comparable to previously described human myeloid populations. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R selectively depleted macrophages with an inflammatory signature but spared a macrophage population that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated of a cDC1-Ccl22 population and gradually increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing. Raw FASTQ sequences have been uploaded to European Nucleotide Archive (Study #: PRJEB34105 (ERP116961))

2020-02-23 | E-MTAB-8832 | biostudies-arrayexpress

Identification of pathogenic TRAIL-expressing innate immune cells during HIV-1 infection in humanized mice by scRNA-seq

Project description:We employed the single-cell RNA sequencing (scRNA-seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-seq on hCD45+hCD3-hCD19- human leukocytes isolated from spleens of humanized NOD/Rag2-/- /γc-/- (NRG) mice transplanted with human CD34+ hematopoietic stem-progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells including plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), macrophage, nature killer (NK) cells and innate lymphoid cells (ILC). HIV-1 infection significantly upregulated genes involved in type-I interferon inflammatory pathways in each of the innate immune subsets. Interestingly, we found that the TNF-related apoptosis-inducing ligand (TRAIL) was upregulated in the innate immune populations including pDC, mDC, macrophage, NK and ILC. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells and defined an important role of TRAIL signaling pathway in HIV-1 induced CD4+ T cell depletion in vivo.

2020-06-04 | GSE148796 | GEO

Identification of a Cxcl10+ monocyte subset with a pathogenic signature in the CNS during auto-immune neuroinflammation

Project description:Multiple Sclerosis (MS) is characterized by pathological inflammation resulting from recruitment of lymphoid and myeloid immune cells from the blood circulation into the central nervous system (CNS). Due to cellular heterogeneity, defining the functional roles of these subsets in acute and chronic stages of MS has been challenging. Here we used index sorting and transcriptional single-cell sequencing to characterize peripheral mononuclear phagocyte infiltrates in the MS mouse model, experimental autoimmune encephalomyelitis (EAE). Based on their transcriptomes, we identified eight monocyte and three dendritic cell subsets during disease pathology with defined characteristics pointing towards distinct functions. Cell ablation identified two specific monocytic subsets with a pathogenic potential. Congenic monocyte transfer experiments combined with indexed-lineage sorting coupled to scRNA-seq established that these pathogenic cells are not descendants of the canonical Ly6C+ monocytes but derived from early myeloid cell progenitors. These results suggest a potential for targeted therapeutic interventions aimed at blocking specific pathogenic monocytic subsets.

2020-04-20 | GSE144317 | GEO

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Affymetrix).

Project description:While most blood lineages are assumed to mature through a single cellular and developmental route downstream of hematopoietic stem cells (HSCs), dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors (CMPs) differentiate into common dendritic cell progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that Interferon regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8-/- bone marrow demonstrated cell-intrinsic defects in the formation of CDPs and all splenic dendritic cell subsets. Irf8-/- CMPs and, unexpectedly, Irf8-/- ALPs produced more neutrophils in vivo than their wild type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context. CMP (Lineage-c-kithiSca-1-CD11c- CD34+ Flk2+CD16/32-CD115- ) or CDP (Lin-c-kitintSca-1-CD34+Flk2+CD16/32-CD115+) were double sorted from the bone marrow of wild type C57BL/6 mice. RNA was extracted from 10,000-30,000 sorted cells using Trizol (Invitrogen) and linear acrylamide (Ambion), amplified using Affymetrix Two-Cycle Amplification and IVT kits (Affymetrix), and hybridized to Affymetrix Mouse Genome 430 2.0 chips.

2012-01-07 | E-GEOD-34892 | biostudies-arrayexpress

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Illumina).

Project description:While most blood lineages are assumed to mature through a single cellular and developmental route downstream of hematopoietic stem cells (HSCs), dendritic cells (DCs) can be derived from both myeloid and lymphoid progenitors in vivo. To determine how distinct progenitors can generate similar downstream lineages, we examined the transcriptional changes that accompany loss of in vivo myeloid potential as common myeloid progenitors (CMPs) differentiate into common dendritic cell progenitors (CDPs), and as lymphoid-primed multipotent progenitors (LMPPs) differentiate into all lymphoid progenitors (ALPs). Microarray studies revealed that Interferon regulatory factor 8 (IRF-8) expression increased during each of these transitions. Competitive reconstitutions using Irf8-/- bone marrow demonstrated cell-intrinsic defects in the formation of CDPs and all splenic dendritic cell subsets. Irf8-/- CMPs and, unexpectedly, Irf8-/- ALPs produced more neutrophils in vivo than their wild type counterparts at the expense of DCs. Retroviral expression of IRF-8 in multiple progenitors led to reduced neutrophil production and increased numbers of DCs, even in the granulocyte-macrophage progenitor (GMP), which does not normally possess conventional DC potential. These data suggest that IRF-8 represses a neutrophil module of development and promotes convergent DC development from multiple lymphoid and myeloid progenitors autonomously of cellular context. CMP (Lineage-c-kithiSca-1-CD11c- CD34+ Flk2+CD16/32-CD115- ) or ALP (Lin-Ly6D-B220-c-kit+Flk2+IL7R?+) were double sorted from the bone marrow of wild type C57BL/6 mice. RNA was extracted from 2,000-15,000 sorted cells using Qiagen RNeasy Mini kit, amplified using Nugen pico-amplification kit , and 750 ng of aRNA was hybridized to Illumina MouseRef-8 v 2.0 bead chips Amy,M,Becker

2012-01-07 | E-GEOD-34915 | biostudies-arrayexpress

Quantitative proteomics analysis of small inputs of human monocytic populations from blood and glioma macrophages

Project description:Many subsets of myeloid cells have been identified over the years, some of which are extremely rare populations. Previously, we identified the optimal protocol for proteomics studies in paucicellular myeloid samples [PXD018872], which was implemented here to investigate cellular relationships of small myeloid cell populations from peripheral blood and glioma material.

2023-02-09 | PXD026604 | Pride

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Illumina).

2012-01-07 | GSE34915 | GEO

IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid progenitors (Affymetrix).

2012-01-07 | GSE34892 | GEO

Existence of conventional dendritic cells in Gallus gallus revealed by comparative gene expression profiling

Project description:The existence of conventional dendritic cells (cDCs) has not yet been demonstrated outside mammals. In this paper, we identified bona fide cDCs in chicken spleen. Comparative profiling of global and of immune response gene expression, morphology, and T cell activation properties show that cDCs and macrophages (MPs) exist as distinct mononuclear phagocytes in chicken, resembling their human and mouse cell counterparts. Using computational analysis, core gene expression signatures for cDCs, MPs, T and B cells across chicken, human and mouse were established, which will facilitate the identification of these subsets in other vertebrates. Overall this study, by extending the newly uncovered cDC and MP paradigm to chicken, suggests that the generation of these two phagocyte lineages occurred before the reptile to mammal and bird transition in evolution. It opens avenues for the design of new vaccines and neutraceuticals that are mandatory for the sustained supply of poultry products in the expanding human population. Four independent replicates of RNA from 4 cellular populations have been purified from histocompatible chicken spleens, based on surface markers and fluorecence cell sorting: putative conventional Dendritic cells (F2+, MHC-II+ cells) ; control B cells (BU-1+ cells; only 3 replicates could be included in the study); T cells (CD3+ cells) and macrophage spleen population (MHC-II+, KUL-01+ cells).

2014-05-01 | E-GEOD-55642 | biostudies-arrayexpress

Comparison of human and mouse dendritic cell subsets by genome-wide expression profiling

Project description:Dendritic cells (DCs) are a complex group of cells which play a critical role in vertebrate immunity. Spleen or lymph node resident DCs are subdivided into conventional DC (cDC) subsets (CD11b and CD8alpha in mouse; BDCA1 and BDCA3 in man) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To bring novel insights into these questions, we sought conserved genetic signatures for these DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes. We show through clustering analysis that all spleen resident DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionary conserved in all these DC subsets. Moreover we identify a large gene expression program shared between mouse and human plasmacytoid DCs, and smaller conserved profiles shared between mouse and human cDC subsets. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs (IKDCs) and lin-CD16+HLA-DR+ cells, which have both been claimed to be DCs, and show that these cells are more closely linked to NK or myeloid cells, respectively. Our study thus provides a unique resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs. Keywords: cell type comparison of wild-type spleen leukocyte subsets, including palsmacytoid dendritic cells, CD8alpha conventional dendritic cells, and CD11b conventional dendritic cells

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