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Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response

1
Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
2
Bonifar d.o.o., Koprska ulica 108A, 1000 Ljubljana, Slovenia
3
Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000 Ljubljana, Slovenia
4
Faculty of Health Sciences, University of Primorska, Polje 42, 6310 Izola, Slovenia
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Vaccines 2020, 8(1), 135; https://doi.org/10.3390/vaccines8010135
Received: 30 January 2020 / Revised: 17 March 2020 / Accepted: 17 March 2020 / Published: 19 March 2020
(This article belongs to the Special Issue Immunization by Electroporation)
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. View Full-Text
Keywords: melanoma cell adhesion molecule; siRNA; gene electrotransfer; irradiation; vascular targeted effect; immune response; mouse melanoma model; mouse carcinoma model melanoma cell adhesion molecule; siRNA; gene electrotransfer; irradiation; vascular targeted effect; immune response; mouse melanoma model; mouse carcinoma model
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MDPI and ACS Style

Kranjc Brezar, S.; Mrak, V.; Bosnjak, M.; Savarin, M.; Sersa, G.; Cemazar, M. 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 2020, 8, 135. https://doi.org/10.3390/vaccines8010135

AMA Style

Kranjc Brezar S, Mrak V, Bosnjak M, Savarin M, Sersa G, Cemazar M. 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. 2020; 8(1):135. https://doi.org/10.3390/vaccines8010135

Chicago/Turabian Style

Kranjc Brezar, Simona, Valter Mrak, Masa Bosnjak, Monika Savarin, Gregor Sersa, and Maja Cemazar. 2020. "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 8, no. 1: 135. https://doi.org/10.3390/vaccines8010135

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