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microRNA modified tumor‐derived exosomes as novel tools for maturation of dendritic cells
Tumor‐derived exosomes (TEX) are known by their immune suppression effects as well as initiation mediators in cancer progression and metastasis. Meanwhile, they are appropriate sources to induce immunity against tumor cells, as consist of tumor specific and associated antigens. The aim of the curren...
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| Published in: | Journal of cellular physiology 2019-06, Vol.234 (6), p.9417-9427 |
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| container_issue | 6 |
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| creator | Taghikhani, Adeleh Hassan, Zuhair Mohammad Ebrahimi, Marzieh Moazzeni, Seyyed‐Mohammad |
| description | Tumor‐derived exosomes (TEX) are known by their immune suppression effects as well as initiation mediators in cancer progression and metastasis. Meanwhile, they are appropriate sources to induce immunity against tumor cells, as consist of tumor specific and associated antigens. The aim of the current study is modifying TEX with microRNA miR‐155, miR‐142, and let‐7i, to enhance their immune stimulation ability and induce potent dendritic cells (DC). For this, exosomes were isolated from mouse mammalian breast cancer cell line; 4T1, and subjected to miR‐155, miR‐142, and let‐7i by electroporation. Immature DCs were generated from mouse bone marrow in the presence of interleukin‐4 (IL‐4) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). To mature DCs, lipopolysaccharide (LPS), TEX, and modified TEX were used. The expression level of miRNAs and their target genes (IL‐6, IL‐17, IL‐1b, TGFβ, SOCS1, KLRK1, IFNγ, and TLR4) was determined. TEX were nanovesicles with spheroid morphology which expressed CD81, CD63, and TSG101, as exosome markers, at protein level. MHCII, CD80, and CD40 as maturation markers were assessed by flow cytometry. Overexpression of miRNAs were confirmed in exosomes and mDCs. Up and downregulation of target genes confirmed the gene network in DC maturation. We found that Let‐7i could efficiently induce the DC maturation, as well as miR‐142 and miR‐155 have enhancing effects. These findings reveal that the modified TEX would be a hopeful cell‐free vaccine for the cancer treatment.
Though there has been tremendous advancement in diagnosis, surgical, chemotherapeutic, radiotherapeutic, and specifically the immunotherapy treatment of cancer, they mostly failed in solid tumors. In this study, we tried to use tumor‐derived exosomes as a source of antigens and modified it with miR‐155, miR‐142, and Let‐7i to enhance its immunostimulatory potential as well as tumor microenvironment remodeling. It is imperative to note that we aimed to combine these properties to increase therapeutic potential of exosomes. |
| doi_str_mv | 10.1002/jcp.27626 |
| format | article |
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Though there has been tremendous advancement in diagnosis, surgical, chemotherapeutic, radiotherapeutic, and specifically the immunotherapy treatment of cancer, they mostly failed in solid tumors. In this study, we tried to use tumor‐derived exosomes as a source of antigens and modified it with miR‐155, miR‐142, and Let‐7i to enhance its immunostimulatory potential as well as tumor microenvironment remodeling. It is imperative to note that we aimed to combine these properties to increase therapeutic potential of exosomes.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.27626</identifier><identifier>PMID: 30362582</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Antigen (tumor-associated) ; Antigens ; Bone marrow ; Breast cancer ; Cancer ; Cancer vaccines ; CD40 antigen ; CD63 antigen ; CD80 antigen ; CD81 antigen ; Cell Death - genetics ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation - genetics ; Cytokines - metabolism ; dendritic cell maturation ; Dendritic cells ; Dendritic Cells - cytology ; Electroporation ; Exosomes ; Exosomes - metabolism ; Flow cytometry ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genes ; Immunity ; Interleukins ; Leukocytes (granulocytic) ; Lipopolysaccharides ; Macrophages ; Markers ; Maturation ; Metastases ; Mice ; microRNA ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Morphology ; Neoplasms - genetics ; Proteins ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; T-Lymphocytes - metabolism ; TLR4 protein ; Toll-like receptors ; Tumor cells ; Tumors ; tumor‐derived exosomes (TEX) ; Vaccines ; γ-Interferon</subject><ispartof>Journal of cellular physiology, 2019-06, Vol.234 (6), p.9417-9427</ispartof><rights>2018 Wiley Periodicals, Inc.</rights><rights>2019 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3536-4a25dea3016a576269f71049ff1d00c4ecb0fd754ea0854c73bfbafa7de4c1373</citedby><cites>FETCH-LOGICAL-c3536-4a25dea3016a576269f71049ff1d00c4ecb0fd754ea0854c73bfbafa7de4c1373</cites><orcidid>0000-0001-9197-1416</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.27626$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.27626$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30362582$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Taghikhani, Adeleh</creatorcontrib><creatorcontrib>Hassan, Zuhair Mohammad</creatorcontrib><creatorcontrib>Ebrahimi, Marzieh</creatorcontrib><creatorcontrib>Moazzeni, Seyyed‐Mohammad</creatorcontrib><title>microRNA modified tumor‐derived exosomes as novel tools for maturation of dendritic cells</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>Tumor‐derived exosomes (TEX) are known by their immune suppression effects as well as initiation mediators in cancer progression and metastasis. Meanwhile, they are appropriate sources to induce immunity against tumor cells, as consist of tumor specific and associated antigens. The aim of the current study is modifying TEX with microRNA miR‐155, miR‐142, and let‐7i, to enhance their immune stimulation ability and induce potent dendritic cells (DC). For this, exosomes were isolated from mouse mammalian breast cancer cell line; 4T1, and subjected to miR‐155, miR‐142, and let‐7i by electroporation. Immature DCs were generated from mouse bone marrow in the presence of interleukin‐4 (IL‐4) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). To mature DCs, lipopolysaccharide (LPS), TEX, and modified TEX were used. The expression level of miRNAs and their target genes (IL‐6, IL‐17, IL‐1b, TGFβ, SOCS1, KLRK1, IFNγ, and TLR4) was determined. TEX were nanovesicles with spheroid morphology which expressed CD81, CD63, and TSG101, as exosome markers, at protein level. MHCII, CD80, and CD40 as maturation markers were assessed by flow cytometry. Overexpression of miRNAs were confirmed in exosomes and mDCs. Up and downregulation of target genes confirmed the gene network in DC maturation. We found that Let‐7i could efficiently induce the DC maturation, as well as miR‐142 and miR‐155 have enhancing effects. These findings reveal that the modified TEX would be a hopeful cell‐free vaccine for the cancer treatment.
Though there has been tremendous advancement in diagnosis, surgical, chemotherapeutic, radiotherapeutic, and specifically the immunotherapy treatment of cancer, they mostly failed in solid tumors. In this study, we tried to use tumor‐derived exosomes as a source of antigens and modified it with miR‐155, miR‐142, and Let‐7i to enhance its immunostimulatory potential as well as tumor microenvironment remodeling. It is imperative to note that we aimed to combine these properties to increase therapeutic potential of exosomes.</description><subject>Animals</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Bone marrow</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer vaccines</subject><subject>CD40 antigen</subject><subject>CD63 antigen</subject><subject>CD80 antigen</subject><subject>CD81 antigen</subject><subject>Cell Death - genetics</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - genetics</subject><subject>Cytokines - metabolism</subject><subject>dendritic cell maturation</subject><subject>Dendritic cells</subject><subject>Dendritic Cells - cytology</subject><subject>Electroporation</subject><subject>Exosomes</subject><subject>Exosomes - metabolism</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Genes</subject><subject>Immunity</subject><subject>Interleukins</subject><subject>Leukocytes (granulocytic)</subject><subject>Lipopolysaccharides</subject><subject>Macrophages</subject><subject>Markers</subject><subject>Maturation</subject><subject>Metastases</subject><subject>Mice</subject><subject>microRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Morphology</subject><subject>Neoplasms - genetics</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>T-Lymphocytes - metabolism</subject><subject>TLR4 protein</subject><subject>Toll-like receptors</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>tumor‐derived exosomes (TEX)</subject><subject>Vaccines</subject><subject>γ-Interferon</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp1kMtKxDAUQIMoOj4W_oAE3OiimjSPTpcy-GRQEV25KJnkBjK0zZi0PnZ-gt_ol5hxRheCq3DJ4XDvQWiXkiNKSH481bOjvJC5XEEDSsoi41Lkq2iQ_mhWCk430GaMU0JIWTK2jjYYYTIXw3yAHhung7-7PsGNN846MLjrGx8-3z8MBPecZnj10TcQsYq49c9Q4877OmLrA25U1wfVOd9ib7GB1gTXOY011HXcRmtW1RF2lu8Wejg7vR9dZOOb88vRyTjTTDCZcZULA4oRKpWYX1HaghJeWksNIZqDnhBrCsFBkaHgumATO1FWFQa4pqxgW-hg4Z0F_9RD7KrGxfkGqgXfxyqnyZluFzKh-3_Qqe9Dm7ZL1JCVQy4lS9ThgkppYgxgq1lwjQpvFSXVvHiVilffxRO7tzT2kwbML_mTOAHHC-DF1fD2v6m6Gt0ulF_KJIuL</recordid><startdate>201906</startdate><enddate>201906</enddate><creator>Taghikhani, Adeleh</creator><creator>Hassan, Zuhair Mohammad</creator><creator>Ebrahimi, Marzieh</creator><creator>Moazzeni, Seyyed‐Mohammad</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9197-1416</orcidid></search><sort><creationdate>201906</creationdate><title>microRNA modified tumor‐derived exosomes as novel tools for maturation of dendritic cells</title><author>Taghikhani, Adeleh ; 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Meanwhile, they are appropriate sources to induce immunity against tumor cells, as consist of tumor specific and associated antigens. The aim of the current study is modifying TEX with microRNA miR‐155, miR‐142, and let‐7i, to enhance their immune stimulation ability and induce potent dendritic cells (DC). For this, exosomes were isolated from mouse mammalian breast cancer cell line; 4T1, and subjected to miR‐155, miR‐142, and let‐7i by electroporation. Immature DCs were generated from mouse bone marrow in the presence of interleukin‐4 (IL‐4) and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). To mature DCs, lipopolysaccharide (LPS), TEX, and modified TEX were used. The expression level of miRNAs and their target genes (IL‐6, IL‐17, IL‐1b, TGFβ, SOCS1, KLRK1, IFNγ, and TLR4) was determined. TEX were nanovesicles with spheroid morphology which expressed CD81, CD63, and TSG101, as exosome markers, at protein level. MHCII, CD80, and CD40 as maturation markers were assessed by flow cytometry. Overexpression of miRNAs were confirmed in exosomes and mDCs. Up and downregulation of target genes confirmed the gene network in DC maturation. We found that Let‐7i could efficiently induce the DC maturation, as well as miR‐142 and miR‐155 have enhancing effects. These findings reveal that the modified TEX would be a hopeful cell‐free vaccine for the cancer treatment.
Though there has been tremendous advancement in diagnosis, surgical, chemotherapeutic, radiotherapeutic, and specifically the immunotherapy treatment of cancer, they mostly failed in solid tumors. In this study, we tried to use tumor‐derived exosomes as a source of antigens and modified it with miR‐155, miR‐142, and Let‐7i to enhance its immunostimulatory potential as well as tumor microenvironment remodeling. It is imperative to note that we aimed to combine these properties to increase therapeutic potential of exosomes.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30362582</pmid><doi>10.1002/jcp.27626</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-9197-1416</orcidid></addata></record> |
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| ispartof | Journal of cellular physiology, 2019-06, Vol.234 (6), p.9417-9427 |
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| subjects | Animals Antigen (tumor-associated) Antigens Bone marrow Breast cancer Cancer Cancer vaccines CD40 antigen CD63 antigen CD80 antigen CD81 antigen Cell Death - genetics Cell Differentiation Cell Line, Tumor Cell Proliferation - genetics Cytokines - metabolism dendritic cell maturation Dendritic cells Dendritic Cells - cytology Electroporation Exosomes Exosomes - metabolism Flow cytometry Gene expression Gene Expression Regulation, Neoplastic Gene Regulatory Networks Genes Immunity Interleukins Leukocytes (granulocytic) Lipopolysaccharides Macrophages Markers Maturation Metastases Mice microRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Morphology Neoplasms - genetics Proteins Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism T-Lymphocytes - metabolism TLR4 protein Toll-like receptors Tumor cells Tumors tumor‐derived exosomes (TEX) Vaccines γ-Interferon |
| title | microRNA modified tumor‐derived exosomes as novel tools for maturation of dendritic cells |
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