Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response
In this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plas...
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| Format: | Article |
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MDPI AG
2020-03-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/8/1/135 |
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| author | Simona Kranjc Brezar Valter Mrak Masa Bosnjak Monika Savarin Gregor Sersa Maja Cemazar |
| author_facet | Simona Kranjc Brezar Valter Mrak Masa Bosnjak Monika Savarin Gregor Sersa Maja Cemazar |
| author_sort | Simona Kranjc Brezar |
| collection | DOAJ |
| description | In this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plasmid DNA in the cytosol-activating DNA sensors. The effects and underlying mechanisms of therapy were evaluated in more immunogenic B16F10 melanoma and less immunogenic TS/A carcinoma. The silencing of MCAM potentiated the effect of irradiation (IR) in both tumor models. Combined therapy resulted in 81% complete responses (CR) in melanoma and 27% CR in carcinoma. Moreover, after the secondary challenge of cured mice, 59% of mice were resistant to challenge with melanoma cells, and none were resistant to carcinoma. Combined therapy reduced the number of blood vessels; induced hypoxia, apoptosis, and necrosis; and reduced cell proliferation in both tumor models. In addition, the significant increase of infiltrating immune cells was observed in both tumor models but more so in melanoma, where the expression of IL-12 and TNF-α was determined as well. Our results indicate that the combined therapy exerts both antiangiogenic and immune responses that contribute to the antitumor effect. However, tumor immunological status is crucial for a sufficient immune system contribution to the overall antitumor effect. |
| first_indexed | 2024-04-11T10:59:02Z |
| format | Article |
| id | doaj.art-cde4ae4c04ec420492b6f9aaece4e4ab |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-04-11T10:59:02Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-cde4ae4c04ec420492b6f9aaece4e4ab2022-12-22T04:28:41ZengMDPI AGVaccines2076-393X2020-03-018113510.3390/vaccines8010135vaccines8010135Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune ResponseSimona Kranjc Brezar0Valter Mrak1Masa Bosnjak2Monika Savarin3Gregor Sersa4Maja Cemazar5Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, SloveniaBonifar d.o.o., Koprska ulica 108A, 1000 Ljubljana, SloveniaDepartment of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, SloveniaDepartment of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, SloveniaDepartment of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, SloveniaDepartment of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, SloveniaIn this study, radiotherapy was combined with the gene electrotransfer (GET) of plasmid encoding shRNA against melanoma cell adhesion molecule (pMCAM) with dual action, which was a vascular-targeted effect mediated by the silencing of MCAM and an immunological effect mediated by the presence of plasmid DNA in the cytosol-activating DNA sensors. The effects and underlying mechanisms of therapy were evaluated in more immunogenic B16F10 melanoma and less immunogenic TS/A carcinoma. The silencing of MCAM potentiated the effect of irradiation (IR) in both tumor models. Combined therapy resulted in 81% complete responses (CR) in melanoma and 27% CR in carcinoma. Moreover, after the secondary challenge of cured mice, 59% of mice were resistant to challenge with melanoma cells, and none were resistant to carcinoma. Combined therapy reduced the number of blood vessels; induced hypoxia, apoptosis, and necrosis; and reduced cell proliferation in both tumor models. In addition, the significant increase of infiltrating immune cells was observed in both tumor models but more so in melanoma, where the expression of IL-12 and TNF-α was determined as well. Our results indicate that the combined therapy exerts both antiangiogenic and immune responses that contribute to the antitumor effect. However, tumor immunological status is crucial for a sufficient immune system contribution to the overall antitumor effect.https://www.mdpi.com/2076-393X/8/1/135melanoma cell adhesion moleculesirnagene electrotransferirradiationvascular targeted effectimmune responsemouse melanoma modelmouse carcinoma model |
| spellingShingle | Simona Kranjc Brezar Valter Mrak Masa Bosnjak Monika Savarin Gregor Sersa Maja Cemazar Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response Vaccines melanoma cell adhesion molecule sirna gene electrotransfer irradiation vascular targeted effect immune response mouse melanoma model mouse carcinoma model |
| title | Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response |
| title_full | Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response |
| title_fullStr | Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response |
| title_full_unstemmed | Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response |
| title_short | Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response |
| title_sort | intratumoral gene electrotransfer of plasmid dna encoding shrna against melanoma cell adhesion molecule radiosensitizes tumors by antivascular effects and activation of an immune response |
| topic | melanoma cell adhesion molecule sirna gene electrotransfer irradiation vascular targeted effect immune response mouse melanoma model mouse carcinoma model |
| url | https://www.mdpi.com/2076-393X/8/1/135 |
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