Coordinate downregulation of multiple MHC class I antigen processing genesin chemical-induced murine tumor cell lines of distinct origin

In murine tumor cell lines, downregulation of MHC class I surface expressio n has been frequently detected, but the underlying molecular mechanisms of such deficiencies have not been defined. In this study, murine tumor cell l ines of different histology derived from spontaneous or from chemical-induc ed tumors were analyzed for the expression of multiple components of the ma jor histocompatibility complex (MHC) class I antigen-processing machinery ( APM), including the peptide transporter TAP, the interferon (IFN)-gamma ind ucible proteasome subunits and several chaperones. The tumor cell lines ana lyzed demonstrated a heterogeneous expression pattern of various APM compon ents. In comparison to control cells an impaired coordinated expression of at least three APM components was detected. In particular, extensive APM de ficiencies were found in cell lines derived from chemical-induced tumors. A strong coordinated downregulation of expression and/or function of TAP, th e low molecular weight proteins (LMP) subunits, the proteasome activator PA 28 and/or tapasin was found in 5 of 10 tumor cells, which was associated wi th impaired MHC class I surface expression. In contrast, the expression of beta (2)-microglobulin (beta (2)-m), PA28 beta, the constitutive proteasome subunits X, Y, Z and of the chaperones calnexin, calreticulin, ER60 and ph ospho disulfide isomerase (PDI) was unaltered or only weakly decreased. The deficient expression of APM components could be corrected by IFN-gamma tre atment, which also reconstituted MHC class I surface expression. However, i mpaired expression of APM molecules appears not to be the only cause of abn ormal MHC class I expression, since it could neither be corrected by the ad dition of exogeneous MHC class I binding peptides nor by incubation at low temperature. These results suggest that one major mechanism of murine tumor cells, in particular chemical-induced tumors, to evade the immune system i s the combined dysregulation of various APM components and other factors, w hich still have to be identified.