IFN‐α₁ gene transfection completely abolishes the tumorigenicity of murine B16 melanoma cells in allogeneic DBA/2 mice and decreases their tumorigenicity in syngeneic C57BL/6 mice

Abstract

The murine B16 melanoma (H-2b) was transfected with a retroviral vector containing the mouse IFN-alpha 1 gene. IFN-alpha 1-transfected cells produced IFN-alpha in vitro and exhibited an altered phenotype characterized by a decreased rate of multiplication, enhanced expression of H-2 antigens, an antiviral state to VSV, and decreased pigmentation. Control and IFN-alpha 1-transfected cells were tested for their ability to grow in syngeneic (H-2b) C57Bl/6 and allogeneic (H-2d) DBA/2 mice. IFN-alpha 1-producing B16 clones were less tumorigenic after s.c., i.p., and i.v. routes of injection than IFN-non-producer B16 clones in syngeneic C57Bl/6 mice. IFN-alpha 1-producing B16 cells were, however, totally rejected by allogeneic DBA/2 mice regardless of the routes and inocula tested, while control B16 cells grew in and killed DBA/2 mice. The total rejection of IFN-alpha 1-transfected B16 cells in allogeneic mice appeared to be dependent on T cells as these cells grew in DBA/2 nude mice. Incubation of IFN-alpha-producing clones with anti-mouse IFN-alpha/beta prior to injection into C57Bl/6 mice did not enhance their tumorigenicity. Likewise, injection of C57Bl/6 and DBA/2 mice with antibody to IFN-alpha/beta did not enhance the tumorigenicity of IFN-alpha 1-transfected cells. C57Bl/6 mice immunized with irradiated IFN-alpha 1 cells were only slightly protected against a subsequent challenge with parental B16 cells. In contrast, DBA/2 mice immunized with irradiated IFN-alpha 1 cells exhibited tumor-specific, long-lasting immunity to subsequent challenge with parental B16 cells.

AKT activation and response to interferon-β in human cancer cells

“…2 Type I interferons, IFN-α and IFN-β, are known to have pleotrophic effects like inhibition of tumor cell growth, stimulation of the immune system, and inhibition of angiogenesis and tissue remodeling. [3][4][5][6][7][8] We and others have demonstrated significant growth inhibition and induction of apoptosis by IFN-β in cancer cells including colorectal cancer.. 7,[9][10][11][12] We have previously reported the induction of TRAIL following adenovirus mediated IFN-β gene therapy and IFN-β protein treatment in colorectal cancer cell lines. 13 In these cells, the induction of TRAIL appeared to be a crucial step in the IFN-β induced apoptosis pathway.…”

Type I consensus interferon (CIFN) gene transfer into human melanoma cells up-regulates p53 and enhances cisplatin-induced apoptosis: implications for new therapeutic strategies with IFN-alpha

“…[7][8][9][10][11][12] Rejection of the IFN-␣-producing tumor cells consistently led to the development of long-lasting tumor-specific immunity which, in some cases, was clearly mediated by CD8 + T lymphocytes. 8 Notably, in a recent study in which we specifically selected a highly metastatic mouse tumor resistant to therapy with large doses of IFN-␣/␤, we found that the genetically modified tumor cells expressing IFN-␣ were efficiently rejected by host-mediated mechanisms when injected into immunocompetent syngeneic mice, suggesting that there might be some advantages in transducing this cytokine gene with respect to the conventional therapy.…”

Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models

“…1,2 In murine models, several studies with genetically modified tumor cells producing IFN-␣ have been previously reported, and the efficiency of IFN-␣ transduction for reducing tumorigenicity has been demonstrated. [3][4][5][6] Rejection of IFN-␣-transduced tumor cells depends on a CD8 + cell-mediated immune response. 3 T lymphocytes are the principal effector cells mediating the antitumor immune responses.…”