Comparative analysis of IFN-gamma B7.1 and antisense TGF-beta gene transfer on the tumorigenicity of a poorly immunogenic metastatic mammary carcinoma

Cancer progression is attributed in part to immune evasion strategies that include lack of co-stimulation, down-regulation of cell surface MHC molecul es, and secretion of immunosuppressive factors, such as transforming, growt h factor-beta (TGF-beta). Gene therapy has been employed to counter these m echanisms of immune evasion by transference of B7.1, IFN-gamma or antisense TGF-beta genes into tumor cells, resulting in cell surface expression of B 7.1, 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 o f their efficacy has not been performed. In this study, we have employed a very aggressive, poorly immunogenic and highly metastatic mammary model, 4T 1, to compare the efficacy of B7.1, IFN-gamma and antisense TGF-beta gene t ransfer in stimulating an anti-tumor response. We demonstrate that both IFN -gamma and antisense TGF-beta gene expression significantly reduced the tum origenicity of these cells compared to mock transduced cells, with IFN-gamm a having a greater effect. In contrast, B7.1 gene transfer did not affect t he tumorigenicity of 4T1 cells. The anti-tumor response directed against an tisense TGF-beta -expressing 4T1 tumors was mediated by CD4(+) and CD8(+) T cells. However, CD8(+) T cells, and not CD4(+) T cells, appeared to mediat e the anti-tumor response against IFN-gamma -expressing tumors. Treatment o f tumor-bearing animals with IFN-gamma or antisense TGF-beta gene-modified tumor cell vaccines reduced the number of clonogenic metastases to the lung s and liver compared to treatment with mock-transduced cells. Finally, in a residual disease model in which the primary tumor was excised and mice wer e vaccinated with irradiated tumor cells, treatment of mice with vaccinatio ns consisting of 4T1 cells expressing; both antisense TGF-beta and IFN-gamm a genes was the most effective in prolonging survival.