Enhancement of immunogenicity of tumor cells by cotransfection with genes encoding antisense insulin-like growth factor-1 and B7.1 molecules

Insulin-like growth factor-1 (IGF-1) is expressed in many tumor cell lines and has a role in both normal cell proliferation and in the growth of cance rs. Tumor cells transfected with a vector encoding an IGF-1 antisense cDNA transcriptional cassette driven by the mouse metallothionein-l promoter bec ome immunogenic and lose their tumorigenicity in syngeneic animals. The enh anced immunogenicity is associated with an up-regulation in the expression of major histocompatibility complex class 1 molecule on cell surfaces. Bloc kade of the expression of IGF-1 in tumor cells by the IGF-1 antisense RNA a pproach is not uniformly effective in the induction of antitumoral protecti ve immunity in low and nonimmunogenic tumor model systems. Here, we report that the immunogenicity of hepa 1-6 hepatoma and SMCC-1 colon carcinoma cel ls, which are poorly immunogenic and unresponsive to antisense IGF-1 gene t ransfer, can be induced by cotransfection with genes encoding antisense IGF -1 and mouse B7.1 molecules. The tumor cells modified in this manner became strongly immunogenic and can be used as a cellular vaccine to induce a pro tective immune response in vivo. Immunization with the transfected tumor ce lls also results in regression of the established hepa 1-6 hepatoma and SMC C-1 colon cancer. The immunity is tumor-specific and is mediated by CD3(+)C D8(+) T cells. Cytotoxic T lymphocytes generated in vitro by priming naive spleen cells and in vivo by immunizing mice with the double-transfected tum or cells specifically lysed autologous rumors cells and were effective in a doptive immunotherapy. The data suggest that modification of tumor cells in vitro by cotransfection with genes encoding antisense IGF-1 and B7.1 molec ules may open a new avenue for cancer immunogene therapy.