Upregulation of antitumor immunity by IL-12 gene-transfected AK-5 tumor cells in vivo

We have earlier demonstrated a significant role for IL-12 in the regression of a rat histiocytic tumor, AK-5. In order to analyze further the antitumo r immunity induced by interleukin (It)-12, we have established IL-12-secret ing tumor cell clones by gene transfection. Significant enhancement in the lytic potential of splenocytes by the culture supernatants containing IL-12 demonstrated retention of biological activity by the tumor-cell-derived cy tokine. Athymic nude mice transplanted subcutaneously with tumor cells engi neered to secret IL-12 showed a significant reduction in tumor size, with e nhanced antibody-dependent cellular cytotoxicity. Analysis of the serum sam ples from animals injected with the IL-12 gene-transfected AK-5 cells on di fferent days revealed a significant increase in circulatory IL-12, interfer on (IFN)-gamma, tumor necrosis factor (TNF)-alpha and antitumor antibodies, ail of which contributed to the reduction in tumor mass. The enhanced prol iferative capacity of splenocytes from these animals indicated the presence of highly activated immune cells in vivo. Similarly, intraperitoneal trans plantation of IL-12 gene-transfected tumor cells in syngeneic Wistar rats i nduced a significant increase in cellular cytotoxicity, with a concomitant reduction in cirulatory IL-12 (p40) protein. Administration of antibodies t o IL-12 and IFN-gamma reduced the expression of the costimulatory molecules B7.1 and B7.2 and the cytolytic effecters granzyme B and Fas-L, suggesting their involvement in IFN-gamma-dependent antitumor immune response induced by IL-12. The present study thus demonstrates that IL-12 gene therapy coul d be among the promising approaches for an effective cancer therapy.