Abstract
Oncolytic viruses armed with therapeutic transgenes of interest show great potential in cancer immunotherapy. Here, a novel oncolytic adenovirus carrying a signal regulatory protein‐α (SIRPα)‐IgG1 Fc fusion gene (termed SG635‐SF) was constructed, which could block the CD47 ‘don't eat me’ signal of cancer cells. A strong promoter sequence (CCAU) was chosen to control the expression of the SF fusion protein, and a 5/35 chimeric fiber was utilized to enhance the efficiency of infection. As a result, SG635‐SF was found to specifically proliferate in hTERT‐positive cancer cells and largely increased the abundance of the SF gene. The SF fusion protein was effectively detected, and CD47 was successfully blocked in SK‐OV3 and HO8910 ovarian cancer cells expressing high levels of CD47. Although the ability to induce cell cycle arrest and cell death was comparable to that of the control empty SG635 oncolytic adenovirus in vitro, the antitumor effect of SG635‐SF was significantly superior to that of SG635 in vivo. Furthermore, CD47 was largely blocked and macrophage infiltration distinctly increased in xenograft tissues of SK‐OV3 cells but not in those of CD47‐negative HepG2 cells, indicating that the enhanced antitumor effect of SG635‐SF was CD47‐dependent. Collectively, these findings highlight a potent antitumor effect of SG635‐SF in the treatment of CD47‐positive cancers.
Highlights
CD47 is a cell-surface transmembrane protein that is broadly expressed in normal tissues and functions as a ‘self’ signal by inhibiting phagocytosis through interaction with signal regulatory protein-a (SIRPa) expressed on macrophages (Matozaki et al, 2009; Oldenborg, 2004; Oldenborg et al, 2000; Reinhold et al, 1995; van den Berg and van der Schoot, 2008)
Since the efficacy of the promoter in a plasmid is critical for the expression of target sequences and varies according to cell type, we used a luciferase reporter system to test the efficacy of a panel of promoters in CD47-high-expressing SK-OV3 and HO8910 ovarian cancer cells
The results showed that CCAU, a novel designed chimeric promoter composed of a human CMV enhancer, mouse CMV enhancer, chicken bactin promoter, and ubiquitin intron in turn, was the optimal candidate given its ability to induce the greatest expression of the target gene in both SK-OV3 and HO8910 cells at 48 h (Fig. 1A)
Summary
CD47 is a cell-surface transmembrane protein that is broadly expressed in normal tissues and functions as a ‘self’ signal by inhibiting phagocytosis through interaction with signal regulatory protein-a (SIRPa) expressed on macrophages (Matozaki et al, 2009; Oldenborg, 2004; Oldenborg et al, 2000; Reinhold et al, 1995; van den Berg and van der Schoot, 2008) This ‘self’ signal has been revealed to form part of the host immune-escape strategy of malignant cells by high-expressing CD47; that is, the ‘self’ signal is harnessed as a ‘don’t eat me’ signal to allow the cancer cell to escape from the host immune system (Chao et al, 2010; Edris et al, 2012; Jaiswal et al, 2009; Weiskopf et al, 2013).
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