CD47 blockade augmentation of Trastuzumab antitumor efficacy dependent upon antibody-dependent-cellular-phagocytosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139492 | GEO | 2019/10/29
REPOSITORIES: GEO
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Project description:CD47 blockade augmentation of Trastuzumab antitumor efficacy dependent upon antibody-dependent-cellular-phagocytosis
| PRJNA579973 | ENA
Project description: Not available
| S-EPMC6975273 | biostudies-literature
Project description:Adoptively transferred T cells and agents designed to block the CD47/SIRPalpha axis are promising cancer therapeutics that activate distinct arms of the immune system. We administered anti-CD47 with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which abrogated therapeutic benefit. anti-CD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPalpha and provided a “don’t-eat-me” signal that was not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following anti-CD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests enhanced potency against solid tumors.
2024-03-13 | GSE261475 | GEO
Project description:Therapeutic antibodies trigger antibody-dependent cellular cytotoxicity (ADCC) of cancer cells and also their antibody-dependent cellular phagocytosis (ADCP) by tumor-associated macrophages (TAMs). We report here our unexpected finding that TAMs that have undergone ADCP of tumor cells induced by therapeutic antibodies display immunosuppressive characteristics and inhibit the proliferation and tumoricidal effects of NK and tumor-specific CD8+ T cells in breast cancers and lymphomas. Mechanistically, we show that DNA released from the phagocytosed tumor cells after ADCP activates caspase 1 inflammasome, leading to IL-1β-mediated PD-L1 and IDO upregulation in these cells. Combined treatment with anti- HER2 antibody and inhibitors of PD-L1 and IDO increased the infiltration of NK and CD8+ T cells and enhanced anti- HER2 therapeutic efficacy in mouse models of HER2+ breast cancers. Furthermore, neo-adjuvant Trastuzumab therapy significantly increased PD-L1 and IDO expression in the TAMs of HER2+ breast cancer patients, which correlate with poor Trastuzumab response and reduced NK and CD8+ T cells in the tumors. Collectively, our findings unveil an unexpected role of ADCP induced by therapeutic antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade may provide synergistic therapeutic effects in cancer patients.
2018-09-04 | GSE119342 | GEO
Project description:Cytokines are key regulators of tumor immune surveillance by controlling immune cell activity. Here, we investigated whether interleukin 4 (IL4) has antileukemic activity via immune-mediated mechanisms in an in vivo murine model of acute myeloid leukemia driven by the MLL-AF9 fusion gene. Although IL4 strongly inhibited leukemia development in immunocompetent mice, the effect was diminished in immune-deficient recipient mice, demonstrating that the antileukemic effect of IL4 in vivo is dependent on the host immune system. Using flow cytometric analysis and immunohistochemistry, we revealed that the antileukemic effect of IL4 coincided with an expansion of F4/80+ macrophages in the bone marrow and spleen. To elucidate whether this macrophage expansion was responsible of the antileukemic effect, we depleted macrophages in vivo with clodronate liposomes. Macrophage depletion eliminated the antileukemic effect of IL4, showing that macrophages mediated the IL4-induced killing of leukemia cells. In addition, IL4 enhanced murine macrophage-mediated phagocytosis of leukemia cells in vitro. Global transcriptomic analysis of macrophages revealed an enrichment of signatures associated with alternatively activated macrophages and increased phagocytosis upon IL4 stimulation. Notably, IL4 concurrently induced Stat6-dependent upregulation of CD47 on leukemia cells, which suppressed macrophage activity. Consistent with this finding, combining CD47 blockade with IL4 stimulation enhanced macrophage-mediated phagocytosis of leukemia cells. Thus, IL4 has two counteracting roles in regulating phagocytosis in mice; enhancing macrophage-mediated killing of leukemia cells, but also inducing CD47 expression that protects target cells from excessive phagocytosis. Taken together, our data suggests that combined strategies that activate macrophages and block CD47 have therapeutic potential in AML.
2021-07-14 | GSE155048 | GEO
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. HuVEC cells were cocultured with exosomes derived either from Jurkat or JinB8 cells culture media. Each condition was done in triplicate. Also, Exosome RNA from Jurkat or JINB8 cells were compared to each other in triplicate.
2014-09-01 | E-GEOD-56825 | biostudies-arrayexpress
Project description:We sequenced untreated BT474 cells, BT474 cells treated for three days with trastuzumab or trastuzumab + pertuzumab, as well as two BT474-derived trastuzumab-resistant pools and two BT474-derived trastuzumab + pertuzumab resistant pools. Resistant pools were generated by culturing BT474 cells in gradually increasing doses of trastuzumab and trastuzumab + pertuzumab over the course of several months and continually maintained in drug.
2020-01-26 | GSE121105 | GEO
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: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: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