Interferon-γ-induced increased sensitivity ofHER2/neu-overexpressing tumor cells to lymphokine-activated killer cell lysis: importance of ICAM-1 in binding and post-binding events

Abstract

Treatment ofHER2/neu-overexpressing target cells with interferon γ(IFNγ) (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 ofHER2/neu expression. In the present study, we show that exposure to another cytokine, tumor necrosis factor α (200 U/ml for 3 days), also decreasedHER2/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 IFNγ 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 ofHER2/neu ⁺ targets.