title: Interferon-gamma-induced increased sensitivity of HER2/neu-overexpressing tumor cells to lymphokine-activated killer cell lysis: importance of ICAM-1 in binding and post-binding events.
abstract: Treatment of HER2/neu-overexpressing target cells with interferon gamma (IFN gamma) (200-2000 U/ml for 3 days) markedly enhances their sensitivity to lymphokine-activated killer (LAK) cell lysis. Increased sensitivity is associated with an up-regulation of intercellular adhesion molecule ICAM-1 determinants and a down-regulation of HER2/neu expression. In the present study, we show that exposure to another cytokine, tumor necrosis factor alpha (200 U/ml for 3 days), also decreased HER2/neu expression but had no effect on LAK cell lysis and ICAM-1 expression. This suggests that down-regulation of oncogene expression is not sufficient by itself to induce an enhanced sensitivity to LAK cell lysis. IFN-induced enhanced lysis was associated with an increased binding between effectors and targets, and antibodies to ICAM-1 as well as its counter-receptor LFA-1, blocked the increased binding and lysis. Treatment with IFN gamma still significantly enhanced lysis even when concanavalin A was added to the assay to induce maximal binding, indicating that a post-binding effect also participated in enhanced cytotoxicity. These post-binding alterations, were also sensitive to blocking with anti-ICAM-1 and anti-LFA-1 antibodies. Treatment with IFN also sensitized targets to lysis by T cells in the presence of lectin but had no effect on the relative resistance of HER2+ cells to lysis mediated by perforin or TNF. Together these data demonstrate the importance of ICAM-1 determinants in binding and post-binding events in the IFN-induced increased lysis of HER2/neu+ targets.
authors.affiliation: Department of Medicine, VA Wadsworth-UCLA Medical Center.
authors.forename: C
authors.initials: C
authors.lastname: Fady
authors.forename: A
authors.initials: A
authors.lastname: Gardner
authors.forename: J F
authors.initials: JF
authors.lastname: Gera
authors.forename: A
authors.initials: A
authors.lastname: Lichtenstein
mesh_terms: D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D015815:Cell Adhesion Molecules; D066246:ErbB Receptors; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases