Resistance ofHER2/neu-overexpressing tumor targets to lymphokine-activated-killer-cell-mediated lysis: evidence for deficiency of binding and post-binding events |
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Authors: | Catherine Fady Agnes Gardner Joseph F Gera Alan Lichtenstein |
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Institution: | (1) Department of Medicine, VA Wadsworth-UCLA Medical Center and Jonsson Comprehensive Cancer Center, 90073 Los Angeles, CA, USA;(2) VA Wadsworth Hospital, 691/W111H, Wilshire and Sawtelle Blvds, 90073 Los Angeles, CA, USA |
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Abstract: | HER2/neu-overexpressing tumor cell lines are relatively resistant to lymphokine-activated killer (LAK) cell cytotoxicity when compared toHER2/neu-nonexpressing lines.HER2/neu
+ targets were also resistant to binding by LAK large granular lymphocytes (LGL) as shown by visualization at the single-cell level, a target monolayer binding assay and in cold target inhibition experiments.HER2/neu
+ LAK-resistant ovarian cell lines demonstrated an absence of ICAM-1 expression while expression of LFA-3, N-CAM, laminin and 1 integrins was comparable to that ofHER2/neu
– targets. In contrast, theHER2/neu
+ breast cell line, SKBR-3, which was also resistant to lysis and binding by LAK LGL, demonstrated normal expression of ICAM-1. Anti-ICAM-1 antibodies blocked binding and lysis ofHER2/neu
– carcinoma targets by LAK cells, further supporting the notion that lack of ICAM-1 expression onHER2/neu
+ cells contributes to their resistance. The modest binding and lysis ofHER2/neu
+ targets by LAK cells was significantly inhibited by anti-LFA-1 antibodies, suggesting the existence of another counter-receptor for LFA-1 onHER2/neu
+ targets. The following also supported deficiencies in post-binding events whenHER2/neu
+ cells resisted the lytic activity of LAK cells: (a) when the relative resistance to effector cell binding was overcome by exogenous lectin,HER2/neu
+ cell lines were still resistant to LAK cytolysis, and (b)HER2/neu
+ targets were resistant to perforin-containing granule extracts obtained from the CTLL-R8 cytotoxic lymphocyte cell line. These results indicate that deficiency in effector binding as well as post-binding events contributes to the resistance ofHER2/neu-overexpressing tumor targets to LAK-cell-mediated lysis.Supported by research funds of the Veteran's Administration, the California Institute for Cancer Research and Jonsson Cancer Center core grant CA 16042 funded by NIH |
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Keywords: | HER2/neu LAK cells Cell adhesion molecule Binding Cytotoxicity |
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