NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering chemotherapeutic drugs and reactivating NK cell functions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA897889 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22177959_1.fastq.gz | Fastqsanger.gz | |||
| SRR22177959_2.fastq.gz | Fastqsanger.gz | |||
| SRR22177960_1.fastq.gz | Fastqsanger.gz | |||
| SRR22177960_2.fastq.gz | Fastqsanger.gz | |||
| SRR22177961_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:INTRODUCTION: Amphiphilic copolymer nanoparticle-encapsulated multi-target chemotherapeutic drugs have attracted considerable attention due to their favorable drug efficiency and potential application prospect. Studies have shown that an amphiphilic copolymer, methoxypoly(ethylene glycol)-poly(lactide-co-glycolide) modified with e-polylysine, and encapsulated with hydrophilic doxorubicin, hydrophobic paclitaxel and survivin siRNA profoundly improved the therapeutic effect both in vitro and in vivo.</br>OBJECTIVES: To investigate how MCF-7 cells would response to the exposure of these nanoparticles over with time and assess the biological effects of these nanoparticles and their encapsulated drugs in a holistic manner.</br>METHODS: MCF-7 cells were treated with PBS, nanocarrier and three encapsulated drugs, respectively. Metabolic alterations associated with nano-drugs exposure were investigated by performing untargeted NMR metabolomics with combination of targeted fatty acids analysis by GC-MS on cell extracts. Altered metabolic pathways were further validated by qRT-PCR approach.</br>RESULTS: Copolymers showed great biocompatibility with cells as it induced transit metabolic disruptions without affecting cell survival rate. The rapid release of encapsulated doxorubicin resulted in inhibition of glycolysis and DNA synthesis, active proteolysis; these metabolic alternations were recovered after 10 h exposure. However, the combination use of multiple drugs consistently induced cell cycle arrest and apoptosis evidenced by reduction in glycolysis, active proteolysis, stimulated O-GlcNAcylation, reduced the PC:GPC ratio and fatty acids accumulation. Prolonged exposure to encapsulated-multiple-drugs also induced oxidative stress to cells.</br>CONCLUSION: These findings provide important insight into the biological effects of nanoparticles and their encapsulated drugs while demonstrate that metabolomics is a powerful approach to evaluate the biological effects of nano-drugs.
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Project description:NK cells are lymphocytes that provide a first defense against viral infections and cancer. They act (i) cytotoxic by killing virus-infected and tumorigenic cells and (ii) immune regulatory by releasing cytokines and chemokines. These innate immune cells are commonly further classified as CD56bright and CD56dim NK cells. Former studies confirmed immune regulatory CD56bright NK cells as progenitors of cytotoxic CD56dim NK cells. CD57 was previously described as T cell marker for senescence and terminal differentiation. Recent studies detected CD57+ and CD57- NK cells among the CD56dim NK cell population and suggested a fully mature developmental status for CD57+ NK cells. The recent NK cell maturation model includes CD34+ hematopoietic stem cells (HSC), which develop into CD56bright NK cells, later into CD56dimCD57- and finally into terminally maturated CD56dimCD57+ (1) (2) (3). The molecular mechanisms of human NK cell differentiation and maturation remain unknown to this date. We performed for the first time a proteomic analysis of these distinct developmental stages of human primary NK cells, isolated from overall 10 healthy human blood donors. CD56bright NK cells versusCD56dim and CD56dimCD57- versus CD56dimCD57+ NK cells were analyzed by using quantitative peptide sequencing, which revealed individual protein signatures (3400 proteins) of these different NK cell developmental stages. Notably, our data support the current NK cell differentiation model by highlighting both strong distinctions between CD56dim/bright NK cells and close relationships between CD57+/- NK cells on the proteomic level. Among the most prominent and conserved regulated proteins, we detected myosin IIa, Calvasculin and Calcyclin with very similar expression patterns. We investigated their sub-cellular localization and observed specific recruitment- and accumulation-events at the NK cell immunological synapse (NKIS) after NK activation.
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