GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity
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PROVIDER: PRJNA819974 | ENA |
REPOSITORIES: ENA
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Project description:Targeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3Kδ/CK1e inhibitor, umbralisib (“U2”-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP), leading to an additive anti-tumour effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93% tumour growth inhibition, with 40% of the animals remaining tumour-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodelling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3Kδ- and CD20-targeting agents in patients with B-NHL.
2022-03-30 | GSE199413 | GEO
Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The gene expression analysis using Nanostring platform was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.
2021-10-13 | GSE177053 | GEO
Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The scRNAseq analysis was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.
2022-04-20 | GSE180296 | GEO
Project description:To identify candidate genes regulated by CD47 Affymetrix Human Genome U133 Plus GeneChip 2.0 HCC cell line Huh7 cells with or without CD47 repressed
2014-06-01 | E-GEOD-47563 | biostudies-arrayexpress
Project description:CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface ‘marker of self’ that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. Using hydrogen-deuterium exchange we show that CD47’s ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface.
2021-07-15 | PXD026458 | Pride
Project description:Elevated CD47 expression in some cancers is associated with decreased survival and limits phagocytic clearance by engaging its counter-receptor SIRPα, but elevated CD47 mRNA expression in human melanomas is associated with improved survival. Gene expression data suggested that recruitment of natural killer (NK) cells, which highly express CD47, into the tumor microenvironment contribute to this correlation. The CD47 ligand thrombospondin-1 inhibited wildtype but not Cd47-/- murine NK cell proliferation and granzyme B and interferon-γ expression in vitro. Cd47-/- NK cells correspondingly showed augmented effector phenotypes. Although, wildtype and Cd47-/- NK cells were equally effective for killing B16 melanoma cells in vitro, Cd47-/- mice exhibited enhanced B16 tumor growth in vivo. Consistent with the human data, tumor-bearing Cd47-/- mice had decreased splenic NK numbers with impaired effector protein expression and elevated exhaustion markers. A pro-apoptotic signature in Cd47-/- NK cells was associated with stress-mediated elevation of mitochondrial proton leak, increased reactive oxygen species and apoptosis. Gene expression profiling identified CD47-dependent transcriptional responses in in NK cells from tumor-bearing mice that regulate systemic NK activation and exhaustion. Treating wildtype mice with a CD47 antibody that blocks thrombospondin-1 binding delayed tumor growth and was associated with increased NK recruitment and increased granzyme B- and interferon-γ levels in intratumoral NK but not CD8+ T cells. Therefore, CD47 in the tumor microenvironment regulates NK-mediated tumor immunity, and therapeutic blockade enhances NK immune function.
2020-04-13 | GSE113876 | GEO
Project description:Panicum virgatum exome capture - 1801
| PRJNA446781 | ENA
Project description:Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells. Treatment with B6H12 antibody inhibited co-immunoprecipitation of EGFR with CD47 and inhibited EGF-induced EGFR tyrosine phosphorylation. B6H12 treatment of bCSC also suppressed asymmetric cell division and cell proliferation and up-regulated caspase 3/7 activity. Correspondingly, caspase-7 cleavage in human breast cancers correlated with CD47 expression. Our data shows that B6H12 specifically targets bCSCs but not differentiated cancer cells, and this CD47 signaling is independent of SIRPα. Three replicates of each condition were generated. Three replicates of each MDA-231 attached cells (differentiated), MDA-231 in suspension cells (bCSC), MDA-231 in suspension cells (bCSC) treated with Control Antibody and MDA-231 in suspension cells (bCSC) treated with B6H12 Antibody.
2016-04-01 | E-GEOD-67966 | biostudies-arrayexpress
Project description:Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid bodies. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- or thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, whereas CD47 ligation by thrombospondin-1 suppresses c-Myc expression. The inhibitory effects of increasing CD47 levels can be overcome by maintaining c-Myc expression and are absent in cells with dysregulated c-Myc. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors. To identify gene expression changes associated with CD47 null cells, we compared the gene expression profile of these cells with WT endothelial cell, CD47 null Embryoid bodies cells and an established Embryonic Stem cell line.
2013-07-10 | E-GEOD-43133 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6380423 | biostudies-literature