title: Modulation of the tumor cell phenotype by IFN-gamma results in resistance of uveal melanoma cells to granule-mediated lysis by cytotoxic lymphocytes.
abstract: IFN-gamma, a pleiotropic immune regulator, is implicated in both tumor immune surveillance and selection of tumor variants resistant to immune control, i.e., immunoediting. In uveal melanoma patients, elevated serum levels of IFN-gamma correlate with the spread of metastasis and represent a negative prognostic marker. Treatment with IFN-gamma boosted the MHC class I presentation machinery in uveal melanoma cells but suppressed their MHC class I-restricted CTL lysis. Tumor cells exposed to IFN-gamma efficiently activated specific CTL but were less susceptible to permeabilization by perforin and exhibited a decreased capacity to bind and incorporate granzyme B. These results define a novel mechanism of resistance to granule-mediated CTL lysis in human tumors. Furthermore, the data suggest that immunoediting is not limited to genetic or epigenetic changes resulting in stable cellular phenotypes but also involves an inducible modulation of tumor cells in response to a microenvironment associated with immune activation.
authors.affiliation: Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Hallermalm
authors.forename: Kazutake
authors.initials: K
authors.lastname: Seki
authors.forename: Anna
authors.initials: A
authors.lastname: De Geer
authors.forename: Bruce
authors.initials: B
authors.lastname: Motyka
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.forename: Jelena
authors.initials: J
authors.lastname: Levitskaya
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000502:physiology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000276:immunology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D054353:Perforin / Q000502:physiology; D011379:Prognosis; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014604:Uveal Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes