BACKGROUND: TRAIL and IFNã are promising anti-cancer cytokines and it has been shown that IFNã may sensitize cancer cells to TRAIL. Adipose derived mesenchymal stem cells (ADSCs) are attractive vehicles for delivering anti-cancer agents. In this study, we evaluated the therapeutic potential of PhiC31 (öC31) recombinase and/or piggyBac transposase (pBt) modified ADSCs expressing either TRAIL, IFNã, or co-expressing TRAIL/IFNã in mouse models of melanoma.METHODS: The expression and bioactivity of mouse IFNã and TRAIL in öC31 and pBt modified cells were confirmed. We examined the effects of modified ADSCs on signal intensity of red fluorescence protein expressed by melanoma cells in subcutaneous tumors or established lung metastases and on survival (6 mice per group). We also conducted a flow cytometric analysis of systemic CD4(+)CD25(+)FOXP3(+) T regulatory cells (Tregs) and histological analysis of melanoma tumors. Data were analyzed by Student t test, ANOVA, and log-rank tests. All statistical tests were two-sided.RESULTS: We demonstrated non-viral DNA-integrating vectors can be used for stable transgene expression. IFNã inhibited melanoma cell growth in vitro probably via IFNã-induced JAK/STAT1 signaling pathway activation. Murine TRAIL induced apoptosis in the human cell lines CAOV-4 and Ej-138, while MCF7 and B16F10 cells appeared to be insensitive to TRAIL. Treatment of melanoma cells with IFNã did not influence their response to TRAIL. In contrast, results from in vivo studies showed that IFNã-expressing ADSCs, engrafted into tumor stroma, inhibited tumor growth and angiogenesis, prevented systemic increase of Tregs, increased PD-L1 expression and CD8+ infiltration (but not interleukin-2+ cells), and prolonged the survival of mice (68 days, 95% confidence interval [CI] = 52 to 86 days compared to 36 days, 95% CI = 29 to 39 days for control, P < .001).CONCLUSIONS: For the first time, we employed DNA integrating vectors for safe and stable modification of MSCs. Our data indicate potential of non-virally modified IFNã-expressing ADSCs for treatment of melanoma through direct effects of IFNã. This study may have a significant role in the management of cancer in the future.
Animals Apoptosis