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

Abstract

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

Inflammation-Induced Chemokine Expression in Uveal Melanoma Cell Lines Stimulates Monocyte Chemotaxis

“…19 Interferon-c exerts a direct effect on UM cell lines: stimulating UM cells with IFN-c resulted in an increased expression of the immunosuppressive molecules indoleamine 2,3-dioxygenase, 20 and PD-L1, 21 the adhesion molecule intracellular adhesion molecule (ICAM) 1, 22 and the inflammationrelated molecules of the HLA classes I and II. [23][24][25] In contrast with many other tumors, in UM, an increased expression of HLA classes I and II is correlated to a worse prognosis. 26,27 It is clear that inflammation along with tumor-infiltrating leucocytes (TIL) is an important characteristic of UM, [5][6][7][8]12,13 but the pathophysiological background of this leucocyte infiltration is not yet known.…”

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

“…Modulation of the IFNg receptor (IFNgRa) expression on the tumor epithelial cells may play a critical role in tumor immunoediting (20), including acquisition of stem cell-like phenotype (21) and resistance to granule-mediated cytotoxic T-lymphocyte killing (22).…”

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

“…These findings suggest that MHC downregulation is not the only cause of immune escape by tumors. It has been shown in a uveal melanoma model that treatment with IFNg boosted MHC class I presentation, but MHC class I-restricted CTL lysis was suppressed (36). Similarly, in human malignant melanomas, low-dose IFNg treatment induced MHC expression, but this expression was not associated with a tumor response (37).…”