ANALYSIS OF THE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGEN PRESENTATION MACHINERY IN NORMAL AND MALIGNANT RENAL-CELLS - EVIDENCE FOR DEFICIENCIES ASSOCIATED WITH TRANSFORMATION AND PROGRESSION

In some human tumors, reduced or defective MHC class I surface express ion has been attributed to functional deficiencies of the genes of the antigen-processing machinery, the proteasome subunits low molecular w eight (LMP)-2 and LMP-7, as well as the peptide transporters associate d with antigen processing (TAP)-1 and TAP-2, Using normal epithelial k idney cells (MZ1851LN) and renal cell carcinoma cell lines established from the primary tumor (MZ1851RC) and a lymph node metastasis (MZ1851 LN) of the same patient, me investigated whether the modulation of MHC class I antigens, TAP and LMP molecules, occurs during transformation and subsequent progression, The mRNA and protein expression of MHC cl ass I heavy and light chain TAP and LMP was strongly reduced in MZ1851 RC when compared to the corresponding normal kidney cells MZ1851NN, an d this suppression was even more pronounced in the metastatic cell lin e MZ1851LN. In addition, the activity of the TAP molecules, as measure d by peptide translocation assays, was also markedly diminished in MZ1 851RC compared to MZ1851NN cells and was further down-regulated in cel ls of the metastatic lesion, MHC class I surface expression was enhanc ed by either culturing MZ1851RC and MZ1851LN cells at 26 degrees C ins tead of 37 degrees C or by incubation of both cell lines with class I- specific binding peptides, whereas MHC class I surface expression of M Z1851NN cells was not affected under these culture conditions, IFN-cu and in particular IFN-gamma treatment enhances the steady-state mRNA a nd/or protein levels of TAP, LMP, and MHC class I genes of MZ1851 cell lines but had no additional effect on the stability of MHC class I su rface expression, These data indicate that malignant transformation an d subsequent in vivo selection of renal tubular cells can lead to the recovery of carcinoma cells that show stable expression of an immune e scape phenotype, Deficiencies associated with this phenotype involve a ll levels of the MHC class I-restricted antigen presentation machinery , are at least partially reversible by IFN treatment, and are even mor e pronounced in cells that had acquired metastatic potential.