Recombinant adenovirus of SEA and CD80 genes driven by MMRE and mouse TERT promoter induce effective antitumor immune responses against different types of tumor cells invitro and invivo.

Abstract

Staphylococcus enterotoxinA (SEA) is a powerful immunostimulant and can stimulate Tcells bearing certain T-cell receptor β-chain variable regions when bound to major histocompatibility complexII molecules. SEA is widely used in research of antitumor therapy. The low affinity T-cell receptor (TCR) interaction with SEA in the absence of MHC classII antigens is sufficient for the induction of cytotoxicity but requires additional CD28/B7 signaling to result in proliferation of resting Tcells. In this study, we constructed recombinant adenovirus (named as Ad-MMRE-mTERT-BIS) carrying membrane-expressing SEA (named as SEAtm) and CD80 driven by Myc-Max response elements (MMRE) and mouse telomerase reverse transcriptase (mTERT) promoter to reduce toxicity and to improve safety and efficiency. We demonstrated that Ad-MMRE-mTERT-BIS could make SEAtm and CD80 to co-express highly on the surface of Hepa1-6 and B16 cells, at low level on the surface of CT26 cells, but not in NIH3T3. Hepa1-6 and B16 cells infected by the recombinant adenovirus induced proliferation of CD4+ and CD8+ Tcells and increased cytokine [interleukin (IL)-2, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] production invitro. Intratumoral injection of Ad-MMRE-mTERT-BIS in hepatoma and melanoma mouse models induced tumor-specific cytotoxic Tcells in the spleen. Moreover, hepatoma and melanoma xenografts were suppressed by treatment with Ad-MMRE-mTERT-BIS and the survival time of treated mice was prolonged. These findings suggest that recombinant adenovirus of SEA and CD80 genes driven by mTERT promoter could induce effective antitumor immune responses against different kinds of tumor cells invitro and invivo.