INTERFERON-GAMMA-INDUCED MHC CLASS-I EXPRESSION AND DEFECTS IN JAK STAT SIGNALING IN METHYLCHOLANTHRENE-INDUCED SARCOMAS/

Seventy-eight uncloned tumour cell lines, each established from a prim ary sarcoma induced with methylcholanthrene in immunocompetent nu/+ BA LB/c and C.B.-17 mice or in immunodeficient nu/nu BALB/c and severe co mbined immunodeficient (SCID) mice, were examined for sensitivity to i nterferon-gamma (IFN-gamma) as measured by tumour cell augmentation of major histocompatibility complex (MHC) class I expression. The tumour cells were cultured with IFN-gamma and their expression of K-d, D-d a nd L-d was measured by fluorescence-activated cell sorter analysis. Al l but three of the 78 tumour Lines up-regulated K-d, D-d and L-d to a variable degree in response to IFN-gamma, indicating that IFN-gamma re sistance is not a common property of these sarcomas. The tumour cell l ines varied greatly in their MHC class I expression before as well as after IFN-gamma stimulation. There was a tendency towards a higher MHC expression after IFN-gamma stimulation in tumour lines from immunocom petent mice compared to immunodeficient mice, but no common maximum MH C class I expression level was found for the 78 tumour cell lines. Thr ee of the tumour lines, all from immunodeficient mice, completely fail ed to respond to IFN-gamma by up-regulating MHC class I expression. Th e same three also displayed absence of IFN-gamma-induced Stat1 beta ty rosine phosphorylation and low Stat1 alpha tyrosine phosphorylation, i ndicating a defect in the signal transduction pathway affecting phosph orylation of Stat1. These findings strongly suggest a link between def ects in Stat1 phosphorylation and the failure to up-regulate MHC class I. In all tumour lines tested, the Stat1 Western blotting revealed a 78 kDa protein (p78) not previously described.