4-1BB (CD137) Ligand Enhanced Anti-Tumor Immune Response against Mouse Forestomach Carcinoma In Vivo

Cancer occurrence and development has been demonstrated to be associated with escape from immune surveillance, and low costimulatory molecules expression has been considered as one of the important reasons for cancer evading the immune system. 4-1BB (CD137) is a costimulatory molecule expressed on the surface of activated T cells. Interaction of 4-1BB with its natural ligand (4-1BBL) expressed on antigen presenting cells (APCs) has been shown to amplify T-cell mediated immunity. We therefore examined whether murine cancer cells expressing 4-1BBL could produce anti-tumor effects in inoculated mice. Mouse forestomach carcinoma (MFC) cells were transfected with 4-1BBL gene (MFC/4-1BBL). The proliferation of the transduced cells in vitro was not different from that of parental cells. However, MFC/4-1BBL cells developed small tumors and induced higher cytotoxicity of tumor infiltration lymphocyte (TIL). Production of cytokines (IFN-γ, TNF-α and IL-2) in serum and cytotoxic T lymphocyte (CTL) activity of splenocytes from mice immunized with mitomycin C (MMC)-treated MFC/4-1BBL cells were significantly higher than that from mice immunized with MMC-treated parental MFC and MFC/ pMKITneo cells. These results suggest that modification of cancer cells with 4-1BBL gene can produce anti-tumor immune responses.