Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines.
Journal - Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE: Abnormalities in the constitutive and interferon (IFN)-gamma-inducible HLA class I surface antigen expression of tumor cells is often associated with an impaired expression of components of the antigen processing machinery (APM). Hence we analysed whether there exists a link between the IFN-gamma signaling pathway, constitutive HLA class I APM component expression and IFN-gamma resistance.EXPERIMENTAL DESIGN: The basal and IFN-gamma-inducible expression profiles of HLA class I APM and IFN-gamma signal transduction cascade components was assessed in melanoma cells by RT-PCR, Western blot analysis and/or flow cytometry, the integrity of the janus kinase (JAK)2 locus by comparative genomic hybridization. JAK2 was transiently overexpressed in JAK2- cells. The effect of IFN-gamma on the cell growth was assessed by XTT assay.RESULTS: Analysis of 8 melanoma cell lines linked the IFN-gamma unresponsiveness of Colo 857 cells determined by lack of inducibility of HLA class I surface expression upon IFN-gamma treatment to a deletion of JAK2 on chromosome 9, while other IFN-gamma signaling pathway components were not affected. In addition, the constitutive HLA class I APM component expression levels were significantly reduced in JAK2- cells. Furthermore, JAK2-deficient cells were also resistant to the antiproliferative effect of IFN-gamma. Transfection of wild type JAK2 into JAK2- Colo 857 not only increased the basal APM expression, but also restored their IFN-gamma sensitivity. CONCLUSIONS: Impaired JAK2 expression in melanoma cells leads to reduced basal expression of MHC class I APM components and impairs their IFN-gamma inducibility, suggesting that malfunctional IFN-gamma signaling might cause HLA class I abnormalities.