Expression of an antisense transforming growth factor-beta1 transgene reduces tumorigenicity of EMT6 mammary tumor cells.

Transforming growth factor-beta (TGF-beta) is a potent immunosuppressive cytokine produced by many tumor cells. Secretion of TGF-beta by malignant cells may therefore be a mechanism by which tumor cells escape destruction by tumor-specific T lymphocytes. In order to evaluate the role of tumor-derived TGF-beta on tumor progression, we have inhibited the production of this cytokine by introducing a gene encoding antisense TGF-beta1 into the EMT6 murine mammary tumor cell line using a retroviral vector (Las-TGF-beta1SN). EMT6 cells transduced with this vector (EMT6as-TGF-beta1) stably expressed the antisense gene and secreted 52% less TGF-beta than did tumor cells transduced with the backbone vector alone. Supernatant fluid recovered from tumor cells expressing the antisense TGF-beta1 gene also exhibited a decreased capacity to inhibit alloantigen-specific cytotoxic T-cell responses in vitro. Furthermore, tumor growth in mice injected with EMT6as-TGF-beta1 tumor cells was inhibited compared to mice injected with control tumor cells. These results demonstrate that expression of antisense TGF-beta1 by transduced EMT6 cells decreases their tumorigenicity and suggest that this approach of eliminating immune suppression is a potentially useful strategy to enhance antitumor responses.