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LV-Induced Dendritic Cells for AML Immunotherapy

ABSTRACT: Wilms’ tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML). Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), GM-CSF and IL-4 was used to transduce human monocytes. The overnight transduction procedure induced the self-differentiation of monocytes into highly viable and immunophenotypically stable “SmartDC/tWT1” (GM-CSF+, IL-4+, WT1+, IL-6+, IL-8+, TNF-?+, MCP-1+, HLA-DR+, CD86+, CCR2+, CCR5+). RNA expression pattern analyses revealed up-regulation of several toll-like receptors, interferons and interferon-stimulated genes in lentivirally-reprogrammed SmartDC/tWT1 in comparison with conventional DCs. Remission samples from a FLT3-ITD+ AML patient and surplus material from the donor lymphocyte infusion (DLI) obtained from the matched related donor were used to produce SmartDC/tWT1. In our donor-patient model, donor T cells expanded with SmartDC/tWT1 showed high reactivity against WT1 and against primary AML. Intracellular processing of WT1 peptides by SmartDC/tWT1 resulted in superior WT1-specific CD8+ cytotoxicity against the primary leukemia blasts than exogenous peptide pulsing. Therefore, SmartDC/tWT1 produced in a single day of ex vivo culture with broad homeostatic, innate immunity, antigenic presentation and cytotoxic T cell stimulation properties can be clinically developed in combination with DLI for boosting anti-leukemia responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37231 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA158959

REPOSITORIES: GEO

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LV-Induced Dendritic Cells for AML Immunotherapy

Project description:WilmsM-bM-^@M-^Y tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML). Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), GM-CSF and IL-4 was used to transduce human monocytes. The overnight transduction procedure induced the self-differentiation of monocytes into highly viable and immunophenotypically stable M-bM-^@M-^\SmartDC/tWT1M-bM-^@M-^] (GM-CSF+, IL-4+, WT1+, IL-6+, IL-8+, TNF-?+, MCP-1+, HLA-DR+, CD86+, CCR2+, CCR5+). RNA expression pattern analyses revealed up-regulation of several toll-like receptors, interferons and interferon-stimulated genes in lentivirally-reprogrammed SmartDC/tWT1 in comparison with conventional DCs. Remission samples from a FLT3-ITD+ AML patient and surplus material from the donor lymphocyte infusion (DLI) obtained from the matched related donor were used to produce SmartDC/tWT1. In our donor-patient model, donor T cells expanded with SmartDC/tWT1 showed high reactivity against WT1 and against primary AML. Intracellular processing of WT1 peptides by SmartDC/tWT1 resulted in superior WT1-specific CD8+ cytotoxicity against the primary leukemia blasts than exogenous peptide pulsing. Therefore, SmartDC/tWT1 produced in a single day of ex vivo culture with broad homeostatic, innate immunity, antigenic presentation and cytotoxic T cell stimulation properties can be clinically developed in combination with DLI for boosting anti-leukemia responses. Seeking to better characterize possible effects of truncated WT1 over-expression in the transcriptional activity of dendritic cells, we compared the gene expression pattern of SmartDC/tWT1 with those of SmartDC and Conventional DC.

2012-12-31 | E-GEOD-37231 | biostudies-arrayexpress

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells

Project description:Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.

2017-12-19 | GSE95770 | GEO

Expression data from in vitro differentiated MDSC

Project description:MDSC (myeloid-derived suppressor cells) can be differentiated in vitro using IL-6 and GM-CSF. To identify the specific role of IL-6 in this process, we used microarray to compare MDSC differentiated with IL-6 and GM-CSF to MDSC differentiated with GM-CSF alone. We have found genes and pathways that are up- or downregulated when IL-6 is present.

2020-08-19 | GSE148293 | GEO

Comparison between CD103+ cDC1s from IL-33-treated Flt3L-BMDCs and GM-CSF-treated Flt3L-BMDCs

Project description:To assess genotypic differences between IL-33-induced CD103+ cDC1s and GM-CSF-induced CD103+ cDC1s IL-33 or GM-CSF was treated at 5 ng/ml on the day 5 of Flt3L-BMDC generation and then the cells were incubated for an additional 5 days Then, we performed RNA sequencing of CD103+ cDC1s isolated from IL-33 or GM-CSF-treated Flt3L-BMDCs

2023-05-30 | GSE226585 | GEO

Human monocyte-derived DCs: effect of IL-4 superkines

Project description:Gene expression induced by IL-4 and IL-4 superkines on CD14+ monocytes cultured in the presence of GM-CSF. Super-4 and KFR signal preferentially through the type I and type II IL-4 receptor, respectively. Five biological replicates (n=5 healthy donors), four conditions: GM-CSF alone or in combination with IL-4, Super-4 or KFR. Two colors: Cy3 for GM-CSF alone, Cy5 for any combination. Cells were cultured for 6 hours with 50 ng/ml of GM-CSF and 20 ng/ml of IL-4, Super-4 or KFR.

2012-09-21 | E-GEOD-40200 | biostudies-arrayexpress

Human monocyte-derived dendritic cells: Control vs Tolerogenic

Project description:Transcriptional profiling of human dendritic cells (DC) comparing control (DC generated with GM-CSF plus IL-4) with three different treatments of tolerogenic (DC generated with GM-CSF plus IL-4 and IL-10, or IL-4, IL-10, and IL-6, or IL-4, IL-10, and TGF-b1)

2009-11-13 | GSE18921 | GEO

The DNA methylation profiles of CD14+ monocytes, dendritic cells and myeloid-derived suppressor cells

Project description:The methylation profiles of bisulfite-modified DNA of human CD14+ monocytes were compared with derived immature dendritic cells (GM-CSF/IL-4 ), myeloid-derived suppressor cells (GM-CSF/IL-4/PGE-2), EP2 antagonized myeloid-derived suppressor cells (GM-CSF/IL-4/PGE-2/ PF 04418948 5 µM), EP4 antagonized myeloid-derived suppressor cells (GM-CSF/IL-4/PGE-2/ L-161,982 5 µM) and EP2 + EP4 antagonized myeloid-derived suppressor cells (GM-CSF/IL-4/PGE-2/PF 04418948 5 µM /L-161,982 5 µM) using the Infinium HumanMethylation450 BeadChips (Illumina, Inc., San Diego, CA,). This platform allows the interrogation of >485,000 methylation sites per sample at single-nucleotide resolution, and comprises an average of 17 CpG sites per gene in the 99% of RefSeq genes. 96% of CpG islands are covered, with additional coverage in CpG island shores and the regions flanking them. The samples were hybridized in the array following the manufacturer’s instructions.

2017-09-11 | GSE83458 | GEO

The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells

Project description:Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-γ-producing CD4+ T cells in Il21r-/-Rag2-/- mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2-/- mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.

2013-02-14 | GSE27161 | GEO

Expression data from responders/nonresponders before/after receiving DLI for relapse of CML s/p BMT

Project description:Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4+ DLI in the pre-tyrosine kinase inhibitor era. We used microarrays to detail the global programme of gene expression underlying T cell infiltration into bone marrow of responders and nonresponders to DLI.

2013-09-30 | GSE49067 | GEO

The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells

Project description:Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive M-NM-1-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-M-NM-3-producing CD4+ T cells in Il21r-/-Rag2-/- mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2-/- mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. Total 6 samples were examined. Splenic dendritic cells were treated with IL-21 and/or GM-CSF studying STAT3 and STAT5B binding in the genome

2013-02-14 | E-GEOD-27161 | biostudies-arrayexpress

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