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A novel tumor-associated myeloid cell population inhibits antigen-specific immune responses in cancer patients

ABSTRACT: Tumor progression is associated with an immunosuppressive microenvironment that consists of several elements, such as regulatory T cells, type 2 macrophages and myeloid-derived suppressor cells. Here, we identify for the first time a BDCA1+CD14+ population of immunosuppressive cells that resides both in the blood and tumor of melanoma patients. We demonstrated that the presence of these cells in dendritic cell (DC)-based anti-tumor vaccines significantly suppresses CD4+ T cells in an antigen-specific manner. In an attempt to reveal the mechanism of this suppressive activity, we noticed that BDCA1+CD14+ cells express elevated levels of the check-point molecule PD-L1, which thereby hinders T cell proliferation. Importantly, although this suppressive BDCA1+CD14+ population expresses markers of both BDCA1+ DCs and monocytes, functional, transcriptome and proteome analyses clearly revealed that they comprise a unique population of cells that is exploited by tumors to evade immunity. Thus, targeting these cells may improve the efficacy of cancer immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75042 | GEO | 2016/08/04

SECONDARY ACCESSION(S): PRJNA302281

REPOSITORIES: GEO

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A novel tumor-associated myeloid cell population inhibits antigen-specific immune responses in cancer patients

Project description:Tumor progression is associated with an immunosuppressive microenvironment that consists of several elements, such as regulatory T cells, type 2 macrophages and myeloid-derived suppressor cells. Here, we identify for the first time a BDCA1+CD14+ population of immunosuppressive cells that resides both in the blood and tumor of melanoma patients. We demonstrated that the presence of these cells in dendritic cell (DC)-based anti-tumor vaccines significantly suppresses CD4+ T cells in an antigen-specific manner. In an attempt to reveal the mechanism of this suppressive activity, we noticed that BDCA1+CD14+ cells express elevated levels of the check-point molecule PD-L1, which thereby hinders T cell proliferation. Importantly, although this suppressive BDCA1+CD14+ population expresses markers of both BDCA1+ DCs and monocytes, functional, transcriptome and proteome analyses clearly revealed that they comprise a unique population of cells that is exploited by tumors to evade immunity. Thus, targeting these cells may improve the efficacy of cancer immunotherapy. mRNA profiles of BDCA1+ DCs, BDCA1+CD14+ cells and monocytes, isolated from 3 healthy volunteers, were generated by deep RNA sequencing using HiSeq 2000 System (TruSeq SBS KIT-HS V3ï¼?Illumina)

2016-08-04 | E-GEOD-75042 | biostudies-arrayexpress

Human inflammatory dendritic cells induce Th17 differentiation

2012-11-01 | GSE40484 | GEO

Human inflammatory dendritic cells induce Th17 differentiation

Project description:Transcriptome analysis of five population of Antigen Presenting Cells: inflammatory macrophages, Inflammatory dendritic cells, Cd14+CD16- monocytes, CD14 dim Cd16+ monocytes and BDCA1+ Dendritic cells. We analyzed transcriptomic profiles from 5 differents DC populations: inflammatory DC and macrophages form inflammatory ascites (ovarian cancer, 4 different donors); CD14+CD16- monocytes, CD14dim CD16+ monocytes and BDCA1+ DC (from 3 different healthy donors) using the Affymetrix Human Gene 1.1 ST platform.

2012-11-01 | E-GEOD-40484 | biostudies-arrayexpress

Transcriptional profile of human neonatal cord blood and adult peripheral blood dendritic cells

Project description:A phenotypically and functinoally distinct subset of human blood dendritic cells expressing CD11b is specific of the neonatal environment. We have employed whole genome microarray expression profiling to identify the specific gene signature of CD11b+ cord blood dendritic cells as compared to their adult peripheral blood counterparts. Peripheral blood adult cDC2 (CD20- CD11c+ CD14- BDCA1+ CD11b- ), neonatal cord blood cDC2 (CD20- CD11c+ CD14- BDCA1+ CD11b-) and neonatal cord blood cDC2b (CD20- CD11c+ CD14- BDCA1+ CD11b+) were FACS purified from BDCA1+ magnetically. Neonatal monocytes (CD11c+ CD14+) and neonatal naive T cells (CD3+ CD4+ CD56- CD25- CD45RO-) were used as controls.

2018-09-21 | GSE104110 | GEO

Transcription profiling of mouse CD11b cells purified from mouse spleen from umor-free and tumor-bearing mice

Project description:Active suppression of tumor-specific T lymphocytes can limit the immune-surveillance and immunotherapy efficacy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+/IL-4RÎ±+, inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-Î³ released from T lymphocytes. CD11b+/IL-4RÎ±+ cells produce IL-13 and IFN-Î³ and integrate the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits are active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors has detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumorinduced immune dysfunctions. Experiment Overall Design: Labeled cRNA extracted from a a total of 9 samples was hybridized to the Affymetrix GeneChip MG-U74Av2 which contains 12,488 probe sets . The 3 control samples represented 3 replicates of RNA extracted from Cd11b cells purified from the spleen of tumor-free mice. The 6 samples obtained from tumor-bearing mice represented 3 replicates each of RNA extracted from Cd11b cells purified from the spleen of tumor-bearing mice. Three out of six samples were incubated for 24 hours in complete medium.

2009-04-29 | E-GEOD-5455 | biostudies-arrayexpress

Identification of monocyte-like precursors of granulocytes as a mechanism for accumulation of PMN-MDSC in cancer

Project description:Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) inhibit immune responses in cancer, limit the effects of therapies and promote tumor cell metastasis. Here, we have identified a new precursor that differentiates into granulocytes in vitro and in vivo yet belong to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPG). Under steady state conditions MLPG were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice. Selective depletion of monocytic cells had no effect on the number of granulocytes present in naïve mice but decreased the population of PMN-MDSC in tumor-bearing mice by 50%. The expansion of MLPG was found to be controlled by the down-regulation of the protein Rb1 and not the IRF8 transcription factor that is known to regulate the expansion of PMN-MDSC from classical granulocytes precursors. In cancer patients, putative MLPG were found within the population of CD15 CD14+HLA-DR-/lo M-MDSC. CXCR1+CD15 CD14+HLA-DR-/lo cells lacked immune suppressive activity but had potential to differentiate to neutrophils in contrast to monocytes and CXCR1- suppressive M-MDSC. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSC.

2019-05-30 | GSE131552 | GEO

Identification of monocyte-like precursors of granulocytes as a mechanism for accumulation of PMN-MDSC in cancer [microarray]

2019-05-30 | GSE131516 | GEO

Immunosuppressive capabilities of mesenchymal stromal cells are maintained under hypoxic growth conditions and after gamma irradiation

Project description:To investigate factors that might influence the T-cell suppressive capabilities of mesenchymal stroma cells, T-cell suppressive and non-suppressive mesenchymal stroma cells were compared. Immunosuppressive capabilities of MSCs was determined via T-cell proliferation assay.

2015-01-20 | E-MTAB-2396 | biostudies-arrayexpress

Gene expression profiling of CD11b purified from mouse spleen (tumor-free and tumor-bearing mice)

Project description:Active suppression of tumor-specific T lymphocytes can limit the immune-surveillance and immunotherapy efficacy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+/IL-4Rα+, inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-γ released from T lymphocytes. CD11b+/IL-4Rα+ cells produce IL-13 and IFN-γ and integrate the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits are active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors has detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumorinduced immune dysfunctions. Keywords: Analysis of Cd11b cells from tumor-free and tumor-bearing mice

2006-10-06 | GSE5455 | GEO

Project description:Myeloid-derived suppressor cells (MDSC) is a heterogeneous population of cells that can negatively regulate T-cell function. As opposed to murine MDSC, which are characterized as Gr-1+CD11b+ cells, human MDSC are not so clearly defined due to lack of specific markers. Our lab has previously identified a new subset of MDSC as CD14+HLA-DR-neg/low cells from PBMC. CD14+HLA-DR-neg/low MDSC not only suppress proliferation and IFN-gamma secretion of autologous T cells, but also induce CD25+Foxp3+ regulatory T cells that are suppressive in vitro, whereas the counterpart CD14+HLA-DR-high monocytes don’t have the effect. In this study, we compare the immune-related gene expression between CD14+HLA-DR-neg/low MDSC and CD14+HLA-DR-high monocytes to better characterize the difference between these two populations and to find new potential specific marker for human MDSC. PBMC were isolated from fresh blood healthy donor by density centrifugation. CD14+ cells were isolated by AutoMACS CD14 microbeads using a AutoMACS (Miltenyi), and then stained with CD14 and HLA-DR antibodies. MDSC and monocytes control cells were sorted as CD14+ HLA-DR-neg/low and CD14+HLA-DR-high cells respectively. The sorted two populations were immediately frozen in liquid nitrogen and shipped to the company on dry ice for RNA isolation and further microarray.

2011-09-08 | E-GEOD-32001 | biostudies-arrayexpress

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