Gene transfer of
Fas ligand (FasL) to
tumor cells has been demonstrated to inhibit
tumor growth in vivo, and neutrophils are primarily responsible for this immunoprotection. The
granulocyte-macrophage colony stimulating factor (
GM-CSF) secreted by
tumor vaccine can recruit dendritic cells (DCs) for efficient antigen presentation to T cells that generate the
tumor-specific response. To investigate whether the combination of FasL and
GM-CSF can efficiently suppress
tumor growth, we have established
Lewis lung carcinoma (LLC-1) cells that are transduced with
GM-CSF (LLC/
GM-CSF), FasL (LLC/FasL) or both genes (LLC/FasL/
GM-CSF) to test their tumorigenic potential in vivo. Mice inoculated with LLC/
GM-CSF display high survival rates along with reduction of
tumor growth. In contrast, none of the mice injected with LLC/FasL or LLC/FasL/
GM-CSF develop
tumors. Specific memory immune response and delayed LLC-1
tumor growth are found in mice immunized with LLC-1/FasL or LLC-1/FasL/
GM-CSF. Furthermore,
therapeutic effects are observed only when LLC-1/FasL/
GM-CSF tumor vaccine is employed to retard growth of preexisting LLC-1
tumors.
Tumor growth is also completely suppressed in mice injected with a mixture of LLC-1 and LLC-1/FasL/
GM-CSF. In addition,
IL-12 production, cytotoxic T-cell activity and
IgG against LLC-1 are manifested in mice injected with LLC/FasL/
GM-CSF. Our data show that FasL-induced pathway triggers expression of proinflammatory
cytokines, including
IL-1 beta,
IL-6, MIP-2 and MCP-1, while
GM-CSF-dependent pathway promotes functional maturation and activation of DCs. Taken together, the results indicate that dual gene-based delivery with FasL and
GM-CSF may serve as a more effective
tumor vaccine to suppress
lung cancer cell growth in vivo.