Cancer progression is attributed in part to immune evasion strategies that include lack of co-stimulation, down-regulation of cell surface MHC molecules, and secretion of immunosuppressive factors, such as
transforming growth factor-beta (
TGF-beta). Gene therapy has been employed to counter these mechanisms of immune evasion by transference of B7.1, IFN-gamma or antisense
TGF-beta genes into
tumor cells, resulting in cell surface expression of B7.1, upregulation of MHC class I and class II molecules, or elimination of
tumor-derived
TGF-beta, respectively. Although each of these transgenes has been shown to alter tumorigenicity in murine models, a direct comparison of their efficacy has not been performed. In this study, we have employed a very aggressive, poorly immunogenic and highly metastatic mammary model, 4T1, to compare the efficacy of B7.1, IFN-gamma and antisense
TGF-beta gene transfer in stimulating an anti-
tumor response. We demonstrate that both IFN-gamma and antisense
TGF-beta gene expression significantly reduced the tumorigenicity of these cells compared to mock transduced cells, with IFN-gamma having a greater effect. In contrast, B7.1 gene transfer did not affect the tumorigenicity of 4T1 cells. The anti-
tumor response directed against antisense
TGF-beta-expressing 4T1
tumors was mediated by CD4+ and CD8+ T cells. However, CD8+ T cells, and not CD4+ T cells, appeared to mediate the anti-
tumor response against IFN-gamma-expressing
tumors. Treatment of
tumor-bearing animals with IFN-gamma or antisense
TGF-beta gene-modified
tumor cell
vaccines reduced the number of clonogenic
metastases to the lungs and liver compared to treatment with mock-transduced cells. Finally, in a residual disease model in which the primary
tumor was excised and mice were vaccinated with irradiated
tumor cells, treatment of mice with vaccinations consisting of 4T1 cells expressing both antisense
TGF-beta and IFN-gamma genes was the most effective in prolonging survival.