NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering chemotherapeutic drugs and reactivating NK cell functions
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217191 | GEO | 2022/11/08
REPOSITORIES: GEO
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Project description:NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering chemotherapeutic drugs and reactivating NK cell functions
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Project description:Exosomes are membranous vesicles actively secreted by almost all cells and they deliver certain intracellular molecules, including nucleic acids, proteins, and lipids, to target cells. They are also considered to be good carriers for drug delivery due to their biocompatibility, high permeability, low immunogenicity, and low toxicity. Exosomes from immune cells were also reported to have immunomodulatory activities. Herein we evaluated the application of exosomes derived from expanded natural killer cells (eNK-EXO) for the treatment of ovarian cancer (OC). We demonstrate that eNK-EXO express typical protein markers of natural killer (NK) cells, can be preferentially uptaken by SKOV3 cells, and display cytotoxicity against OC cells. Furthermore, eNK-EXO loaded with cisplatin could sensitize drug-resistant OC cells to the anti-proliferation effect of cisplatin. In addition, we show that eNK-EXO could activate NK cells from immunosuppressive tumor microenvironment, the mechanism of which is explored by transcriptional analysis. In summary, eNK-EXO exhibit anti-tumor activity against OC on its own, could be used to deliver cisplatin and enhance its cytotoxic effect against drug-resistant OC cells and also reverse the immunosuppression of NK cells, which may lead to great prospect of using eNK-EXO in the treatment of OC in the clinic. Our work also builds a strong foundation for further evaluation of eNK-EXO in other solid tumor therapies.
| S-EPMC9892755 | biostudies-literature
Project description:Studies of chimeric antigen receptor (CAR)-T and -Natural killer (NK) cells have shown promising results in treating hematological malignancies. However, there are still obstacles to effectively treating solid tumors. These include the challenges of CAR-T cell homing and infiltration, the presence of immunosuppressive microenvironments, and the potential for antigen escape in solid tumors. To overcome the known limitations of immune cell therapy, we engineered human induced pluripotent stem cell (hiPSC)-derived NK (eNK) cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D-DAP10 complex. We introduced the six genes into hiPSCs using the piggyBac system and stimulated them to differentiate into NK cells. Overexpression of NKG2D complex and high-affinity CD16 enhanced the antitumor function of the eNK cells. Overexpression of IL-15 prolonged the persistence of the eNK cells in vitro and in vivo. Forced expression of CCR2B enhanced eNK cell tumor infiltration. Forced expression of CCL19 endowed the eNK cells with the ability to recruit dendritic cells. We found that the eNK cells were able to lyse HLA-E-expressing tumor cells, but not normal human cells. These proof-of-concept studies demonstrate the promise of our eNK cells as a novel adoptive cell therapy product for the treatment of solid tumors.
2025-06-10 | GSE247437 | GEO
Project description:Human NK cells from the decidua basalis of gravid uteri (dNK) and from cycling endometrium (eNK) of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing ~47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets. Freshly isolated NK cells were obtained by FACS sorting. 4 dNK and 5 eNK samples were obtained form independent donors. dNK cells were isolated from the decidua basalis of first trimester placentas and sorted as CD3-, CD16-, CD56+ cells. eNK cells were obtained from non-affected regions of cycling endometrium of donor women undergoing hysterectomy and were sorted as CD45+, CD56+, CD3- cells . The preliminary patient diagnoses included genital prolapse, fibroids, cervical dysplasia, or menorrhagia. All cycling endometrium samples were from the secretory phase of the cycle with exception of sample eNK_S6 that was from the proliferative phase.
2010-03-09 | E-GEOD-20499 | biostudies-arrayexpress
Project description:Human NK cells from the decidua basalis of gravid uteri (dNK) and from cycling endometrium (eNK) of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing ~47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets.
2010-02-25 | GSE20499 | GEO
Project description:Exosomes are endogenous extracellular vesicles (30-100 nm) composed with membrane lipid bilayer which carry vesicular proteins, enzymes, mRNA, miRNA and nucleic acids. They act as messengers for intra- and inter-cellular communication. In addition to their physiological roles, exosomes have the potential to encapsulate and deliver small chemotherapeutic drugs and biological molecules such as proteins and nucleic acid-based drugs to the recipient tissue or organs. Due to their biological properties, exosomes have better organotropism, homing capacity, cellular uptake and cargo release ability than other synthetic nano-drug carriers such as liposomes, micelles and nanogels. The secretion of tumor-derived exosomes is increased in the hypoxic and acidic tumor microenvironment, which can be used as a target for nontoxic and nonimmunogenic drug delivery vehicles for various cancers. Moreover, exosomes have the potential to carry both hydrophilic and hydrophobic chemotherapeutic drugs, bypass RES effect and bypass BBB. Exosomes can be isolated from other types of EVs and cell debris based on their size, density and specific surface proteins through ultracentrifugation, density gradient separation, precipitation, immunoaffinity interaction and gel filtration. Drugs can be loaded into exosomes at the biogenesis stage or with the isolated exosomes by incubation, electroporation, extrusion or sonication methods. Finally, exosomal cargo vehicles can be characterized by ultrastructural microscopic analysis. In this review we intend to summarize the inception, structure and function of the exosomes, role of exosomes in immunological regulation and cancer, methods of isolation and characterization of exosomes and products under clinical trials. This review will provide an inclusive insight of exosomes in drug delivery.
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Project description:Natural killer (NK) cells are a type of innate lymphocytes that play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms involving TRAIL, Fas Ligand, cytokine secretion, perforin, and granzymes. In addition, extracellular vesicles (EVs), including exosomes derived from NK cells (NK-EVs), possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells in a granzyme B independent manner. In addition, small RNA-seq and mass spectrometry analyses indicate that miRNA and protein profiles in EVs are altered by cytokine stimulation. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings reveal novel characteristics of NK-EVs and the mechanism of their incorporation into target cells.
2021-09-09 | PXD018982 | Pride
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:Hyperglycemia is a recognized risk factor for cardiovascular complications in diabetes. While hyperglycemia is known to cause microRNA dysregulation that contributes to cellular activation, whether it can do so through intercellular communication via extracellular vesicles (EVs) is not known. We investigated whether EVs produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/−mice with exosomes produced by bone marrow‐derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Repeated infusion of BMDM–HG-exo led to a robust increase in hematopoiesis leading to augmented circulating myeloid cell numbers. Four weeks of BMDM–HG-exo infusions increased atherosclerotic lesion sizes with an accumulation of macrophage and apoptotic cells in the aortic root. Transcriptome-wide analysis of naïve cultured macrophages treated with BMDM–HG-exo showed an upregulation of genes associated with cell proliferation. Furthermore, BMDM–HG-exo reprogramed energy metabolism in recipient macrophages with an upregulation of glycolytic activity. Plasma EVs isolated from human subjects with type II diabetes exerted similar cell signaling when incubated with cultured human macrophages. Lastly, profiling microRNA in BMDM–HG-exo and human diabetic plasma EVs converged on miR-486 as commonly enriched. In conclusion, our findings show that EVs serve to communicate detrimental
2021-08-18 | GSE162961 | GEO
Project description:Hyperglycemia is a recognized risk factor for cardiovascular complications in diabetes. While hyperglycemia is known to cause microRNA dysregulation that contributes to cellular activation, whether it can do so through intercellular communication via extracellular vesicles (EVs) is not known. We investigated whether EVs produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/−mice with exosomes produced by bone marrow‐derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Repeated infusion of BMDM–HG-exo led to a robust increase in hematopoiesis leading to augmented circulating myeloid cell numbers. Four weeks of BMDM–HG-exo infusions increased atherosclerotic lesion sizes with an accumulation of macrophage and apoptotic cells in the aortic root. Transcriptome-wide analysis of naïve cultured macrophages treated with BMDM–HG-exo showed an upregulation of genes associated with cell proliferation. Furthermore, BMDM–HG-exo reprogramed energy metabolism in recipient macrophages with an upregulation of glycolytic activity. Plasma EVs isolated from human subjects with type II diabetes exerted similar cell signaling when incubated with cultured human macrophages. Lastly, profiling microRNA in BMDM–HG-exo and human diabetic plasma EVs converged on miR-486 as commonly enriched. In conclusion, our findings show that EVs serve to communicate detrimental
2021-08-18 | GSE162958 | GEO