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Braz J Med Biol Res
2020 Feb 14;533:e8876. doi: 10.1590/1414-431X20198876.
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p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro.
Da-Costa RC
,
Vieira IL
,
Hunger A
,
Tamura RE
,
Strauss BE
.
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The immune stimulatory and anti-neoplastic functions of type I interferon have long been applied for the treatment of melanoma. However, the systemic application of high levels of this recombinant protein is often met with toxicity. An approach that provides localized, yet transient, production of type I interferon may overcome this limitation. We propose that the use of mesenchymal stem cells (MSCs) as delivery vehicles for the production of interferon-β (IFNβ) may be beneficial when applied together with our cancer gene therapy approach. In our previous studies, we have shown that adenovirus-mediated gene therapy with IFNβ was especially effective in combination with p19Arf gene transfer, resulting in immunogenic cell death. Here we showed that MSCs derived from mouse adipose tissue were susceptible to transduction with adenovirus, expressed the transgene reliably, and yet were not especially sensitive to IFNβ production. MSCs used to produce IFNβ inhibited B16 mouse melanoma cells in a co-culture assay. Moreover, the presence of p19Arf in the B16 cells sensitizes them to the IFNβ produced by the MSCs. These data represent a critical demonstration of the use of MSCs as carriers of adenovirus encoding IFNβ and applied as an anti-cancer strategy in combination with p19Arf gene therapy.
Figure 2. Mesenchymal stem cells (MSCs) producing interferon-β (IFNβ) inhibited co-cultured B16 mouse melanoma cells. MSCs were either not transduced (Control) or transduced with AdRGD-CMV-LacZ (LacZ) or AdRGD-PG-IFNβ (IFNβ) at the indicated multiplicity of infection (1000 or 2000) and then co-cultured with B16 cells with stable expression of eGFP (B16-GFP) and, 96 h later, each cell population was counted based on the presence or absence of eGFP expression. Quantification of the (A) MSC or (B) B16-GFP populations is reported as the average and standard error from three independent experiments, normalized by the value obtained for the Control group. ***P<0.001, statistical analysis was performed comparing individual experimental conditions with the control using Student's t-test. GFP: green fluorescent protein.
Figure 3. p19Arf sensitizes B16 cells to interferon-β (IFNβ) produced by mesenchymal stem cells (MSCs). MSCs were either not transduced (MSC) or transduced with AdRGD-CMV-LacZ (MSC LacZ) or AdRGD-PG-IFNβ (MSC IFNβ) and then co-cultured with B16 cells with stable expression of eGFP (B16-GFP) that were also either not transduced (B16) or transduced with either AdRGD-CMV-LacZ (B16 LacZ) or AdRGD-PG-p19 (B16 p19). At the indicated time points, cells were photographed and the B16 cell population was counted based on presence of eGFP expression. Data are reported as the average and standard error from three independent experiments. **P<0.01 comparing individual experimental conditions with the control (MSC LacZ + B16 LacZ, 72 h) using the Student's t-test. ##P<0.01 comparing individual experimental conditions with MSC IFNβ + B16 p19 (72 h) using Student's t-test.
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