Compromised anti-tumor responses in tumor necrosis factor-α knockout mice

Abstract

The response of lymphokine-activated killer (LAK) and natural killer (NK) cells from mice lacking tumor necrosis factor-α (TNF-α-/- mice) was impaired in cytotoxicity assays against various tumor cell targets. Furthermore, allogeneic cytotoxic T lymphocyte (CTL) responses were also impaired as compared to TNF-α+/+ littermates (control mice). Cytotoxicity was restored both upon in vitro incubation of TNF-α-/- lymphocytes with recombinant TNF-α (rTNF-α) or upon in vivo treatment of TNF-α-/- mice with rTNF-α. Using combinations of monoclonal antibodies we were able to show that TNF-α-/- effector lymphocytes exhibit both perforin- and Fas ligand-based cytotoxicity. Furthermore, upon in vivo administration of rTNF-α these effectors, in addition to perforin and Fas ligand, are also armed with TNF-α cytotoxic molecules, thus resembling to the cytotoxic effectors from control mice. In a tumor model, immunized TNF-α-/- mice failed to reject the syngeneic fibrosarcoma MC57X, but did so when injected with rTNF-α. In vivo administration of anti-TNF-α mAb neutralized the effect of rTNF-α supporting the growth of MC57X cells. Our data provide novel evidence for TNF-α as an essential factor in (i) controlling cytotoxicity in vitro and in vivo and (ii) promoting tumor rejection in vivo.