An experimental study on antitumor immuno-gene therapy using dendritic cells genetically modified to express the tumor antigen gene and cytokine gene

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In present study, we examined therapeutic efficacy of the immunotherapy using dendritic cells (DCs) genetically engineered to express the tumor antigen, comparing to the immunotherapy using DCs pulsed with the tumor antigen peptide in CT26 tumor models. Moreover, DCs were transduced simultaneously with tumor antigen gene and GM-CSF gene, and we assessed the augmenting effect of cotransduction with GM-CSF gene on therapeutic vaccine therapy. Bone marrow-derived murine DCs were adenovirally transduced with natural tumor antigen gp70 gene of BALB/c-derived CT26 (DC-AxCAgp70), and cotransduced with murine GM-CSF (DC-AxCAgp70/mGM-CSF). On the other hand, DCs were pulsed with AH-1 which is immunodominant peptide of the gp70 (DC/AH-1). The cytotoxic T lymphocyte (CTL) activities induced in the mice immunized with DCs-AxCAgp70 showed significantly higher (40%) than that in the mice immunized with DC/AH-1 (24%)(E/T : 50). Furthermore, CTL activities were enhanced in the mice immunized with DC-AxCAgp70/mGM-CSF (86%). In the subcutaneous tumor model and the orthotopic colon cancer model of CT26, the vaccine therapy using DC-AxCAgp70 showed much more remarkable inhibition of tumor growth than the vaccination using DC/AH-1 (p<0.0001), which was reflected in resulting in the prolongation of the survival periods. Antitumor responses were augmented by cotransduction with mGM-CSF gene to DC-AxCAgp70. CC chemokine receptor 7 mRNA expression on DCs, which would play an important role in the migration of DCs to regional lymph nodes was induced by adenoviral transduction with gp70 gene, and more enhanced by cotransduction with mGM-CSF gene. In contrast, it was not detected in AH-1-pulsed DCs. These results suggested that the vaccination using DCs transduced with both the tumor antigen gene and cytokine gene could be a more potent strategy for therapeutic antitumor immunotherapy.