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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

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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

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