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Modulation of the Tumor Cell Phenotype by IFN- Results in Resistance of Uveal Melanoma Cells to Granule-Mediated Lysis by Cytotoxic Lymphocytes¹

Kristian Hallermalm^*, Kazutake Seki^*, Anna De Geer^*, Bruce Motyka, R. Chris Bleackley, Martine J. Jager, Christopher J. Froelich, Rolf Kiessling^*, Victor Levitsky^¶ and Jelena Levitskaya^2,*

^* Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada; Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Division of Rheumatology, Department of Medicine, Evanston Northwestern Healthcare Research Institute and Northwestern University Feinberg School of Medicine, Evanston, IL; and ^¶ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

IFN-, 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- correlate with the spread of metastasis and represent a negative prognostic marker. Treatment with IFN- 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work has been supported by grants from the Swedish Cancer Society, the Cancer Society of Stockholm, and the King Gustav the Vth Jubilee Fund.

² Address correspondence and reprint requests to Dr. Jelena Levitskaya at her current address: Department of Molecular Microbiology and Immunology, W. Harry Feinstone, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205. E-mail address: jelevits{at}jhsph.edu

³ Abbreviations used in this paper: UM, uveal melanoma; LCL, lymphoblastoid cell line; grB, granzyme B; FasL, Fas ligand; PI, propidium iodide; TMRE, tetramethylrhodamine ethyl ester perchlorate; R2, receptor 2; CI-MPR, calcium-dependent mannose 6-phosphate receptor.