Effects of beta-2 microglobulin anti-sense oligonucleotides on sensitivity of HER2/neu oncogene-expressing and nonexpressing target cells to lymphocyte-mediated lysis.
The mechanism by which HER2/neu overexpressing tumor cells resist NK, LAK, and LDCC cytotoxic lymphocytes was investigated. Resistance was not explained by a delay in kinetics of lysis, concurrent resistance to TNF, or a diminished expression of the transferrin receptor. HLA-class I expression, however, was markedly elevated compared to HER2 nonexpressing targets suggesting a reason for resistance. To test the role of class I, we selectively decreased expression by incubation of targets with beta-2 microglobulin anti-sense oligonucleotides. Anti-sense-treated HER2+ targets, displaying levels of class I comparable to HER2- targets, were still markedly resistant to cytotoxic effectors. Down-regulation of class I expression in HER2- carcinoma cells also had no effect on sensitivity to cytotoxicity by anti-sense treatment of Raji and U937 targets resulted in enhanced sensitivity to NK and LAK effectors but not to T cells mediating LDCC. These data indicate resistance to cytotoxicity in HER2-expressing targets cannot be solely explained by heightened expression of class I. The data also support the concept that class I expression regulates sensitivity to NK and LAK cells (but not LDCC effectors) in selected targets.
Department of Medicine, V.A. Wadsworth UCLA Medical Center.
A
A
Lichtenstein
C
C
Fady
J F
JF
Gera
A
A
Gardner
V R
VR
Chazin
D
D
Kelley
J
J
Berenson
D000818:Animals; D001483:Base Sequence; D003602:Cytotoxicity, Immunologic; D016373:DNA, Antisense / Q000276:immunology* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D006680:HLA Antigens / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000032:analysis*; D018719:Erb-b2 Receptor Tyrosine Kinases; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology*
D016373:DNA, Antisense; D006680:HLA Antigens; D009841:Oligonucleotides; D009856:Oncogene Proteins, Viral; D018719:Erb-b2 Receptor Tyrosine Kinases; D001613:beta 2-Microglobulin