title: HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway.
abstract: Because of its amplification and/or overexpression in many human tumors, the HER-2/neu proto-oncogene represents an attractive target for T-cell-mediated vaccination strategies. However, overexpression of oncogenes is often associated with defective expression of components of the MHC class I antigen-processing machinery (APM), thereby resulting in an immune escape phenotype of oncogene-transformed cells. To determine whether HER-2/neu influences the MHC class I antigen-processing pathway, the expression pattern of different APM components was examined in murine in vitro models of constitutive and tetracycline-controlled HER-2/neu expression. In comparison with HER-2/neu(-) control cells, HER-2/neu(+) fibroblasts exhibit reduced levels of MHC class I surface antigens that were associated with impaired expression and/or function of the peptide transporter associated with antigen processing, the proteasome subunits low molecular weight protein 2 and low molecular weight protein 10, the proteasome activators PA28alpha and PA28beta, and tapasin. These APM abnormalities resulted in reduced sensitivity to lysis by CTLs. The HER-2/neu-mediated immune escape phenotype could be corrected by IFN-gamma treatment. The clinical relevance of this finding was supported by an inverse correlation between HER-2/neu and the peptide transporter associated with antigen-processing protein expression as determined by immunhistochemical analysis of a series of HER-2/neu(-) and HER-2/neu(+) breast cancer specimens. Thus, a functional link between deficient APM component expression and HER-2/neu overexpression is proposed that might influence the design of HER-2/neu-targeted T-cell-based immunotherapeutic strategies.
authors.affiliation: Third Department of Internal Medicine and Pathology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Herrmann
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Ingo
authors.initials: I
authors.lastname: Drexler
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.forename: Jan
authors.initials: J
authors.lastname: Hengstler
authors.forename: Ursula
authors.initials: U
authors.lastname: Wollscheid
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D005786:Gene Expression Regulation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
chemical_list: D015395:Histocompatibility Antigens Class I; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715470:MAS1 protein, human