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  • NKG2D ligands  (8)
Keywords
  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; DISEASE ; PROTEIN ; PROTEINS ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; RESPONSES ; INFECTION ; MECHANISM ; mechanisms ; BINDING ; RECOGNITION ; ACID ; antibodies ; antibody ; PARTICLES ; TARGET ; virus ; NECROSIS-FACTOR-ALPHA ; MELANOMA ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; NKG2D ; SIALIC-ACID ; INTERFERON ; melanoma cells ; RECEPTORS ; CYTOTOXICITY ; APOPTOSIS-INDUCING LIGAND ; GAMMA ; MELANOMA-CELLS ; HEPARAN-SULFATE ; Newcastle disease virus ; USA ; macrophage ; ANTITUMOR VACCINATION ; NECROSIS ; paramyxovirus ; virology ; MODIFIED TUMOR-CELLS ; CYTOTOXICITY RECEPTORS ; NATURAL-KILLER-CELL ; NKG2D ligands ; PARTICLE ; CYTOMEGALOVIRUS UL16 GLYCOPROTEIN ; INFECTED CELLS ; INTRACELLULAR RETENTION ; KILLER-CELL ; natural killer cell
    Abstract: The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3 zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV
    Type of Publication: Journal article published
    PubMed ID: 19515783
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  • 2
    Keywords: EXPRESSION ; IDENTIFICATION ; CANCER-CELLS ; NATURAL-KILLER-CELLS ; HISTONE DEACETYLASE INHIBITORS ; MESSENGER-RNA STABILITY ; SODIUM VALPROATE ; NKG2D ligands ; CYTOTOXICITY RECEPTOR NKP30 ; CHAIN-B
    Abstract: Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7-family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6 we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and mRNA expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after siRNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells, which has implications for potential cancer treatments combining immunotherapy with HDACi.
    Type of Publication: Journal article published
    PubMed ID: 23801635
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  • 3
    Keywords: CUTTING EDGE ; DOWN-REGULATION ; ANTITUMOR-ACTIVITY ; BREAST-CANCER ; UP-REGULATION ; NK cells ; myeloid cells ; NKG2D ligands ; MALIGNANT DISEASES ; CHAIN-RELATED MOLECULE
    Abstract: Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell-mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell-based cancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 24780758
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  • 4
    Keywords: CANCER ; IN-VIVO ; TRIAL ; NK cells ; MALIGNANT-MELANOMA ; RECEPTORS ; ADOPTIVE TRANSFER ; NKG2D ligands ; VIVO EXPANSION ; LINE NK-92
    Abstract: During the recent years, immunotherapy has obtained substantial impact on the clinical treatment of melanoma. Besides promising approaches based on T lymphocytes, natural killer (NK) cells have gained more and more attention as anti-melanoma effector cells. NK cell activation is inhibited by HLA class I molecules expressed by target cells, so they preferentially attack tumor cells that express low levels of HLA class I. Partial or complete loss of HLA class I expression is a frequent event during the development of melanoma. In parallel, ligands for activating NK cell receptors become induced upon malignant transformation. Thus, melanoma cells are often efficiently recognized and lysed by NK cells at least in vitro. In vivo, however, melanomas have developed multiple sophisticated strategies to escape from NK cell mediated attack. Several novel approaches aim at harnessing NK cells to treat melanoma patients and to counteract existing tumor escape mechanisms. This review summarizes the most recent advances in the field.
    Type of Publication: Journal article published
    PubMed ID: 25640488
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  • 5
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    Oncogene 27 (45), 5944-5958 
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; PATHWAY ; DISTINCT ; TISSUE ; TUMORS ; LINES ; TIME ; ACTIVATION ; LIGAND ; RESPONSES ; CUTTING EDGE ; MECHANISM ; TISSUES ; CD8(+) T-CELLS ; DENDRITIC CELLS ; mechanisms ; BIOLOGY ; CELL-LINES ; DOWN-REGULATION ; MOLECULAR-BIOLOGY ; TARGET ; genetics ; CELL-LINE ; LINE ; ONCOGENE ; LIGANDS ; NK cells ; NKG2D ; RAE-1 ; STRATEGIES ; CD8(+) ; immune response ; IMMUNE-RESPONSE ; IMMUNITY ; HEALTHY ; heredity ; TUMOR-CELL-LINES ; tumor immunology ; signaling ; molecular biology ; molecular ; ONCOLOGY ; review ; RE ; GAMMA ; ACUTE MYELOID-LEUKEMIA ; TUMOR TISSUE ; LEVEL ; immunology ; ENGLAND ; NKG2D RECEPTOR ; UP-TO-DATE ; response ; ANTITUMOR RESPONSES ; CELL BIOLOGY ; HUMAN HEPATOCELLULAR CARCINOMAS ; NATURAL-KILLER-CELL ; MHC-CLASS-I ; natural killer ; ACTIVATING RECEPTOR ; MIC-A ; NKG2D ligands ; RETINOIC-ACID ; ULBP
    Abstract: The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, gamma delta(+) and CD8(+) T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed
    Type of Publication: Journal article published
    PubMed ID: 18836475
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  • 6
    Keywords: CELLS ; IN-VITRO ; Germany ; IN-VIVO ; THERAPY ; MECHANISM ; DENDRITIC CELLS ; PROGNOSTIC-SIGNIFICANCE ; PERIPHERAL-BLOOD LYMPHOCYTES ; tumor immunology ; REGULATORY T-CELLS ; COLORECTAL-CANCER PATIENTS ; tumor microenvironment ; OVARIAN-CARCINOMA ; SUPPRESSOR-CELLS ; Natural killer cells ; NKG2D ligands ; MATURE NK-CELLS ; MOLONEY LEUKEMIA-CELLS
    Abstract: Natural killer (NK) cells play an important role in the innate immune response against cancer, in particular in the elimination of tumor metastases and small tumors. NK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, such as MHC class I. Thus, we assume that these tumors might be good targets for NK cell-mediated attack. In vitro, NK cells directly kill tumor cells and release soluble factors that affect both innate and adaptive immune responses. To date, in vivo NK cell activation during tumor progression, the influence of the tumor microenvironment on NK cells, and the mechanisms that interfere with their effector function in cancer patients are not completely understood. This review summarizes our current knowledge of NK cells in solid tumors. We will discuss the impact of novel insights into NK cell responses against tumors on the design of NK cell-based therapies.
    Type of Publication: Journal article published
    PubMed ID: 21502747
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  • 7
    Keywords: LUNG-CANCER ; T-CELLS ; COLORECTAL-CANCER ; CERVICAL-CANCER ; NATURAL-KILLER-CELLS ; RECEPTORS ; CLINICAL-APPLICATIONS ; NKG2D ligands ; MEDIATED CYTOLYSIS ; MULTICELLULAR SPHEROIDS
    Abstract: BACKGROUND: The complex cellular networks within tumors, the cytokine milieu, and tumor immune escape mechanisms affecting infiltration and anti-tumor activity of immune cells are of great interest to understand tumor formation and to decipher novel access points for cancer therapy. However, cellular in vitro assays, which rely on monolayer cultures of mammalian cell lines, neglect the three-dimensional architecture of a tumor, thus limiting their validity for the in vivo situation. METHODS: Three-dimensional in vivo-like tumor spheroid were established from human cervical carcinoma cell lines as proof of concept to investigate infiltration and cytotoxicity of NK cells in a 96-well plate format, which is applicable for high-throughput screening. Tumor spheroids were monitored for NK cell infiltration and cytotoxicity by flow cytometry. Infiltrated NK cells, could be recovered by magnetic cell separation. RESULTS: The tumor spheroids were stable over several days with minor alterations in phenotypic appearance. The tumor spheroids expressed high levels of cellular ligands for the natural killer (NK) group 2D receptor (NKG2D), mediating spheroid destruction by primary human NK cells. Interestingly, destruction of a three-dimensional tumor spheroid took much longer when compared to the parental monolayer cultures. Moreover, destruction of tumor spheroids was accompanied by infiltration of a fraction of NK cells, which could be recovered at high purity. CONCLUSION: Tumor spheroids represent a versatile in vivo-like model system to study cytotoxicity and infiltration of immune cells in high-throughput screening. This system might proof useful for the investigation of the modulatory potential of soluble factors and cells of the tumor microenvironment on immune cell activity as well as profiling of patient-/donor-derived immune cells to personalize cellular immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 25933805
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  • 8
    Keywords: PEPTIDE ; RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; VITRO ; MOLECULES ; TISSUE ; ACCUMULATION ; LINES ; ACTIVATION ; LIGAND ; CONTRAST ; T-CELLS ; CELL-LINES ; DOWN-REGULATION ; MOLECULE ; TARGET ; IN-SITU ; NEOPLASIA ; PROGRESSION ; NUMBER ; cervical cancer ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; CELL-LINE ; LYMPHOCYTES ; PEPTIDES ; LIGANDS ; CLASS-I ; HUMAN-PAPILLOMAVIRUS ; NATURAL-KILLER-CELLS ; NK cells ; EPITHELIAL-CELLS ; CERVICAL-CARCINOMA ; CARCINOMAS ; PROGNOSTIC-SIGNIFICANCE ; IMMUNOTHERAPY ; intraepithelial neoplasia ; T-LYMPHOCYTES ; T lymphocyte ; BIOPSY ; T lymphocytes ; ONCOLOGY ; RE ; USA ; LOSSES ; NKG2D RECEPTOR ; viral ; NOV ; NK-CELLS ; NKG2D ligands ; DNAM-1 ligands ; I-RELATED CHAIN ; PARTICLE VACCINE ; QUADRIVALENT VACCINE
    Abstract: Human papillomavirus-induced cervical carcinomas often show impaired expression of MHC class I molecules resulting in the inability of tumor cells to directly present viral peptides to cytotoxic T lymphocytes. Loss of MHC class I expression combined with the expression of activating NK cell receptor ligands renders tumor cells potentially susceptible to NK cell attack. Thus, in this study, we analyzed the expression of activating NK cell receptor ligands, NK cell accumulation and activation status in situ in normal ectocervical tissue (NCT), cervical intraepithelial neoplasia (CIN) and squamous cervical carcinoma (CxCa). We observed that expression of the DNAM-I ligand CD155 was frequently upregulated in CxCa, but not in CIN. The NKG2D ligand MICA was upregulated in fewer CxCa biopsies. In contrast, another NKG2D ligand ULBP2 was preferentially expressed in differentiated epithelial cells of NCT. Increased numbers of NK cells were detected in CIN as compared to NCT and CxCa. Expression of activating NK cell receptor ligands combined with loss of MHC class I was not correlated with enhanced NK cell accumulation or activation status. Furthermore, we demonstrate that cervical cancer cell lines are killed by the NK cell line, NKL, in a NKG2D- and DNAM-1-dependent manner in vitro. Since a significant number of CxCa biopsies showed low MHC class I expression combined with high expression of one or more of the tested activating NK cell receptor ligands, we conclude that CxCa might be a promising target for NK cell-based adoptive immunotherapy. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18712710
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