280. RANTES and TARC Enhanced the Antitumor Immune Effects of GM-CSF

Top of pageAbstract Previously we demonstrated the gene transduction of granulocyte- colony stimulating-factor (GM-CSF) gene into murine monocytic leukemia cell line of WEHI3B eliminated the tumorigenesity in vivo. The rejection process of subcutaneous tumor was as follows; transient tumor growth peaked around 10 day after tumor injection, then the tumors were rejected within a week. We analyzed the gene expression of the transiently established tumor masses by the serial analysis of gene expression (SAGE) method to identify molecules associated with the antitumor effect. We identified that chemokine genes of TARC and RANTES were preferentially expressed in the GM-CSF-transduced tumors and the contribution of the two genes to the regression of GM-CSF-transduced tumors was suggested. To confirm the finding, we observed in vivo tumor formation of WEHI-3B cells transduced with a retroviral vector expressing murine GM- CSF, TARC, RANTES, GM-CSF+TARC or GM-CSF+RANTES, respectively. 1.0x10|[circ]|6|[circ]|cells of each transduced cell group and non- transduced cell group were inoculated subcutaneously into syngeneic mice, female BALB/c (n=20 or 21). Then tumorigenecity and survival rate were observed. Both of the combination of GM-CSF with TARC or RANTES gene transduction profoundly inhibited tumor formation. In addition, the 2 groups demonstrated significantly longer survival than GM-CSF transduced group. Immunohistochemistry of the tumor section at day 10 after inoculation revealed more significant contribution of CD4+ T cells to tumor regression in both of the TARC/GM-CSF and RANTES/ GM-CSF-transduced cell tumors than GM-CSF transduced cell tumors. More CD11c positive cells were observed in RANTES/GM-CSF-transduced cell tumors than GM-CSF transduced cell tumors. To determine the therapeutic effects of tumor vaccines producing GM-CSF and TARC and/or RANTES against established tumor, in vivo mouse experiments are under way.