Dataset Information

Dendritic Cell-Targeted pH-Responsive Extracellular Vesicles for Anticancer Vaccination.

ABSTRACT: Immunotherapy can potentially treat cancers on a patient-dependent manner. Most of the efforts expended on anticancer vaccination parallel the efforts expended on prototypical immunization in infectious diseases. In this study, we designed and synthesized pH-responsive extracellular vesicles (EVs) coupled with hyaluronic acid (HA), 3-(diethylamino)propylamine (DEAP), monophosphoryl lipid A (MPLA), and mucin 1 peptide (MUC1), referred to as HDEA@EVAT. HDEA@EVAT potentiated the differentiation and maturation of monocytes into dendritic cells (DCs) and the priming of CD8? T-cells for cancer therapy. MPLA and HA enabled HDEA@EVAT to interact with the toll-like receptor 4 and the CD44 receptor on DCs, followed by endosomal escape, owing to the protonation of pH-sensitive DEAP on the EV in conjunction with MUC1 release. The MUC1 was then processed and presented to DCs to activate CD8? T-cells for additional anticancer-related immune reactions. Our findings support the anticancer vaccine activity by which HDEA@EVAT expedites the interaction between DCs and CD8? T-cells by inducing DC-targeted maturation and by presenting the cancer-associated peptide MUC1.

SUBMITTER: Lee H

PROVIDER: S-EPMC6410067 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Dendritic Cell-Targeted pH-Responsive Extracellular Vesicles for Anticancer Vaccination.

Lee Hyuk H Park Hongsuk H Yu Hyeong Sup HS Na Kun K Oh Kyung Taek KT Lee Eun Seong ES

Pharmaceutics 20190127 2

Immunotherapy can potentially treat cancers on a patient-dependent manner. Most of the efforts expended on anticancer vaccination parallel the efforts expended on prototypical immunization in infectious diseases. In this study, we designed and synthesized pH-responsive extracellular vesicles (EVs) coupled with hyaluronic acid (HA), 3-(diethylamino)propylamine (DEAP), monophosphoryl lipid A (MPLA), and mucin 1 peptide (MUC1), referred to as HDEA@EVAT. HDEA@EVAT potentiated the differentiation and ...[more]

PMID: 30691225

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Project description:Mesenchymal stromal cells (MSCs) are potent regulators of immune responses largely through paracrine signaling. MSC secreted extracellular vesicles (MSC-EVs) are increasingly recognized as the key paracrine factors responsible for the biological and therapeutic function of MSCs. We report the first comprehensive study demonstrating the immunomodulatory effect of MSC-EVs on dendritic cell (DC) maturation and function. MSC-EVs were isolated from MSC conditioned media using differential ultracentrifugation. Human monocyte-derived DCs were generated in the absence or presence of MSC-EVs (20 ug/ml) then subjected to phenotypic and functional analysis in vitro. MSC-EV treatment impaired antigen uptake by immature DCs and halted DC maturation resulting in reduced expression of the maturation and activation markers CD83, CD38, and CD80, decreased secretion of pro-inflammatory cytokines IL-6 and IL-12p70 and increased production of anti-inflammatory cytokine TGF-β. MSC-EV treated DCs also demonstrated a diminished CCR 7 expression after LPS stimulation, coupled with a significantly reduced ability to migrate toward the CCR7-ligand CCL21, although they were still able to stimulate allogeneic T cell proliferation in vitro. Through microRNA profiling we have identified 49 microRNAs, which were significantly enriched in MSC-EVs compared to their parent MSCs. MicroRNAs with known effect on DC maturation and functions, including miR-21-5p, miR-142-3p, miR-223-3p, and miR-126-3p, were detected within the top 10 most enriched miRNAs in MSC-EVs, with MiR-21-5p as the third highest expressed miRNA in MSC-EVs. In silico analysis revealed that miR-21-5p targets the CCR7 gene for degradation. To verify these observations, DCs were transfected with miR-21-5p mimics and analyzed for their ability to migrate toward the CCR7-ligand CCL21 in vitro. MiR-21-5p mimic transfected DCs showed a clear trend of reduced CCR7 expression and a significantly decreased migratory ability toward the CCL21. Our findings suggest that MSC-EVs are able to recapitulate MSC mediated DC modulation and MSC-EV enclosed microRNAs may represent a novel mechanism through which MSCs modulate DC functions. As MSCs are currently used in clinical trials to treat numerous diseases associated with immune dysregulation, such as graft-versus-host disease and inflammatory bowel disease, our data provide novel evidence to inform potential future application of MSC-EVs as a cell-free therapeutic agent.

Project description:The dengue virus (DENV), transmitted by Aedes spp. mosquitoes, is one of the most important arboviral infections in the world. Dengue begins as a febrile condition, and in certain patients, it can evolve severe clinical outcomes, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The reasons why certain patients develop DHF or DSS have not been thoroughly elucidated to date, and both patient and viral factors have been implicated. Previous work has shown that a severe immune dysfunction involving dendritic cells and T cells plays a key role in increasing the disease severity, especially in secondary heterologous infections. Extracellular vesicles (EVs) are membranous particles that are secreted by several cell types involved in homeostatic and pathological processes. Secretion of EVs by infected cells can enhance immune responses or favor viral evasion. In this study, we compare the molecular content of EVs that are secreted by human primary dendritic cells under different conditions: uninfected or infected with DENV3 strains isolated from patients with different infection phenotypes (a severe case involving DSS and a mild case). Human monocyte-derived dendritic cells (mdDCs) were infected with the dengue virus strains DENV3 5532 (severe) or DENV3 290 (mild), and the EVs were isolated. The presence of cup-shaped EVs was confirmed by electron microscopy and immunostaining with CD9, CD81, and CD83. The RNA content from the mdDC-infected cells contained several mRNAs and miRNAs related to immune responses compared to the EVs from mock-infected mdDCs. A number of these RNAs were detected exclusively during infection with DENV3 290 or DENV3 5532. This result suggests that the differential immune modulation of mdDCs by dengue strains can be achieved through the EV pathway. Additionally, we observed an association of EVs with DENV-infectious particles that seem to be protected from antibodies targeting the DENV envelope protein. We also showed that EVs derived from cells treated with IFN alpha have a protective effect against DENV infection in other cells. These results suggested that during DENV infection, the EV pathway could be exploited to favor viral viability, although immune mechanisms to counteract viral infection can also involve DC-derived EVs.

Dataset Information

Dendritic Cell-Targeted pH-Responsive Extracellular Vesicles for Anticancer Vaccination.

Publications

Dendritic Cell-Targeted pH-Responsive Extracellular Vesicles for Anticancer Vaccination.

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