SIGNALING THROUGH THE LYMPHOTOXIN BETA-RECEPTOR INDUCES THE DEATH OF SOME ADENOCARCINOMA TUMOR LINES

Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-b eta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological f unction of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cel l death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT -alpha and a converted form of LT-beta wherein the normally type II LT -beta membrane protein was changed to a type I secreted form. Recombin ant LT-alpha(1)/beta(2) was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizi ng agent interferon (IFN) gamma. When immobilized on a plastic surface , anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of the se cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-be ta-R mAbs were also identified that inhibited ligand-induced cell deat h, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta- R antibody combined with human IFN-gamma arrested tumor growth. The de lineation of a biological signaling event mediated by the LT-beta-R op ens a window for further studies on its immunological role, and furthe rmore, activation of the LT-beta-R may have an application in tumor th erapy.