INTERFERON-GAMMA-INDUCED INTERCELLULAR-ADHESION MOLECULE-1 - EXPRESSION ON HUMAN TUMOR-CELLS ENHANCES BIFUNCTIONAL ANTIBODY-MEDIATED LYSIS THROUGH A LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 DEPENDENT MECHANISM

Antitumor x anti-CD3 bifunctional antibodies (BFAs) affect tumor cell lysis by activating and physically linking T-cells and tumor cells. Si nce tumor target antigen expression does not correlate with susceptibi lity to BFA-mediated tumor cytotoxicity, we investigated the role of c ell adhesion molecules as accessory molecules. In 3 human colon tumor cell lines (LS174T, WIDR, and COLO205), recombinant interferon-gamma ( rIFN-gamma) consistently increased BFA-mediated tumor cell lysis by cu ltured peripheral blood lymphocytes and consistently increased tumor c ell expression of intercellular adhesion molecule-1 (ICAM-1). Using ce ll conjugation assays, we demonstrated that ICAM-1 and lymphocyte func tion-associated antigen-1 (LFA-1) interactions were important for effe ctor-to-target cell conjugate formation and demonstrated that tumor ce ll pretreatment with rIFN-gamma enhanced cell conjugate formation. Whe reas anti-LFA-1 blocked all BFA-mediated tumor lysis and conjugate for mation, anti-ICAM-1 blocked only the enhancing effects of rIFN-gamma f or both cytolysis and conjugate formation. Although BFAs were shown to provide effector-to-target cell bridging, LFA-1 was found to be a com mon critical element required for BFA-mediated cell conjugation and ly sis. ICAM-1, which was augmented by rIFN-gamma, appears to be only one of several ligands interacting with LFA-1. These results provide one explanation as to why high expression of tumor-associated antigen alon e does not predict the susceptibility to BFA-mediated lysis and provid es further support for the concept of combined modality immune therapi es.