Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

Abstract

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of ab CD81 T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-c (IFN-c) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-c treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-c treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-c-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-c, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. ' 2008 Wiley-Liss, Inc.Key words: melanoma; MHC class I loss; natural killer cell; NKG2D; interferon-c Malignant melanoma is well characterized for its recognition by cytotoxic ab CD8 1 T lymphocytes (CTLs) that respond to tumorassociated peptide antigens presented in the complex with classical MHC class I surface molecules.1 Indeed, CTLs can eliminate metastatic tumors in melanoma patients, as demonstrated in different clinical trials of adoptive T cell transfer.2 The efficiency of tumor cell killing is determined by the strength of the antigen signal and co-stimulatory signals sensed by different activating receptors. Very recently, it was demonstrated that triggering of the co-stimulatory receptor NKG2D on CTLs strongly enhanced the T cells capacity to kill melanoma cells. 3Besides the importance of antigen-specific CTLs in immune surveillance of melanoma, one can assume that early detection and elimination of premalignant and malignant cutaneous melanocytes might be a major task of skin-resident innate NK cells and innate-like Vd1 gd T lymphocytes. 4 Both effectors are capable of preventing and inhibiting the growth of autologous human melanoma grafted into the skin of severe combined immunodeficient (SCID) mice.5 Interestingly, the receptor NKG2D is constitutively expressed on Vd1 gd T cells present in normal human sk...

Identification of a cellular ligand for the natural cytotoxicity receptor NKp44

“…34 On the other hand, stimulation by cytokines (type I and II interferons, IL-2, IL-12, IL-15, IL-18, and transforming growth factor-b) does not affect the regulation of NKp44L (data not shown), but can induce some NKG2D ligands. 46,47 These data suggest, similar to other ligands for activating NK receptors, that NKp44L transmits a danger signal in certain pathological situations, including certain infections and cancers, to induce the lysis of target cells by activated NKp44 1 NK cells.…”

NK Cells Are Required for Dendritic Cell–Based Immunotherapy at the Time of Tumor Challenge

“…Even in the absence of vaccination, MHC-I is upregulated in an IFN-g-dependent fashion on implanted B16 tumor cells within hours, and this expression is maintained during in vivo growth (44,47). IFN-g also leads to NKG2D ligand downregulation on B16 (48). These features may protect B16 from direct NK cell cytolysis.…”

RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells

“…The effect of chronic elevated IFN-c levels is unknown, but, if associated with impaired upregulation of MICA in response to RSV infection, could lead to impaired viral clearance. It was recently reported that in human tumour cells, concurrently with the upregulation of surface MHC class I, IFN-c downregulates the levels of surface MICA [25,26]. Interestingly, chronic obstructive pulmonary disease (COPD) is associated with an exaggerated type 1 immune cell inflammatory infiltrate [7,27].…”