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Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells.
Int J Cancer. 2009 Apr 01; 124(7):1594-604.IJ

Abstract

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) 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-gamma (IFN-gamma) 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-gamma 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-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells.

Authors+Show Affiliations

Division of Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center, Heidelberg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19089914

Citation

Schwinn, Nicole, et al. "Interferon-gamma Down-regulates NKG2D Ligand Expression and Impairs the NKG2D-mediated Cytolysis of MHC Class I-deficient Melanoma By Natural Killer Cells." International Journal of Cancer, vol. 124, no. 7, 2009, pp. 1594-604.
Schwinn N, Vokhminova D, Sucker A, et al. Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells. Int J Cancer. 2009;124(7):1594-604.
Schwinn, N., Vokhminova, D., Sucker, A., Textor, S., Striegel, S., Moll, I., Nausch, N., Tuettenberg, J., Steinle, A., Cerwenka, A., Schadendorf, D., & Paschen, A. (2009). Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells. International Journal of Cancer, 124(7), 1594-604. https://doi.org/10.1002/ijc.24098
Schwinn N, et al. Interferon-gamma Down-regulates NKG2D Ligand Expression and Impairs the NKG2D-mediated Cytolysis of MHC Class I-deficient Melanoma By Natural Killer Cells. Int J Cancer. 2009 Apr 1;124(7):1594-604. PubMed PMID: 19089914.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells. AU - Schwinn,Nicole, AU - Vokhminova,Daria, AU - Sucker,Antje, AU - Textor,Sonja, AU - Striegel,Sandra, AU - Moll,Iris, AU - Nausch,Norman, AU - Tuettenberg,Jochen, AU - Steinle,Alexander, AU - Cerwenka,Adelheid, AU - Schadendorf,Dirk, AU - Paschen,Annette, PY - 2008/12/18/entrez PY - 2008/12/18/pubmed PY - 2009/3/4/medline SP - 1594 EP - 604 JF - International journal of cancer JO - Int. J. Cancer VL - 124 IS - 7 N2 - NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alphabeta CD8(+) 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-gamma (IFN-gamma) 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-gamma 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-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/19089914/Interferon_gamma_down_regulates_NKG2D_ligand_expression_and_impairs_the_NKG2D_mediated_cytolysis_of_MHC_class_I_deficient_melanoma_by_natural_killer_cells_ L2 - https://doi.org/10.1002/ijc.24098 DB - PRIME DP - Unbound Medicine ER -