HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway.
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.
Herrmann
Felix
F
Third Department of Internal Medicine and Pathology, Johannes Gutenberg-University, Mainz, Germany.
Lehr
Hans-Anton
HA
Drexler
Ingo
I
Sutter
Gerd
G
Hengstler
Jan
J
Wollscheid
Ursula
U
Seliger
Barbara
B
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
D015395:Histocompatibility Antigens Class I; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715470:MAS1 protein, human