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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; PROTEINS ; transcription ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; COMPLEX ; LIGAND ; RESPONSES ; COMPLEXES ; CUTTING EDGE ; IFN-GAMMA ; MACROPHAGES ; TRANSCRIPTION FACTOR ; AP-1 ; TISSUES ; SKIN ; TARGET ; STRESS ; STRESS-RESPONSE ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; CD8(+) ; IMMUNE-RESPONSE ; CELL-SURFACE ; RE ; TUMORIGENESIS ; RHEUMATOID-ARTHRITIS ; LEVEL ; MICE LACKING JUNB ; immunology ; TRANSCRIPTION FACTOR AP-1 ; NKG2D RECEPTOR
    Abstract: The activating receptor NKG2D and its ligands RAE-1 play an important role in the NK, gamma delta(+), and CD8(+) T cell-mediated immune response to tumors. Expression levels of RAE-1 on target cells have to be tightly controlled to allow immune cell activation against tumors but to avoid destruction of healthy tissues. In this study, we report that cell surface expression of RAE-1 epsilon is greatly enhanced on cells lacking JunB, a subunit of the transcription complex AP-1. Furthermore, tissue-specific junB knockout mice respond to 12-O-tetradecanoyl-phorbol-13-acetate, a potent AP-1 activator, with markedly increased and sustained epidermal RAE-1 epsilon expression. Accordingly, junB-deficient cells are efficiently killed via NKG2D by NK cells and induce IFN-gamma production. Our data indicate that the transcription factor AP-1, which is involved in tumorigenesis and cellular stress responses, regulates RAE-1 epsilon. Thus, up-regulated RAE-1 epsilon expression due to low levels of JunB could alert immune cells to tumors and stressed cells
    Type of Publication: Journal article published
    PubMed ID: 16365389
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; TYROSINE KINASE ; PROTEIN ; RNA ; cell line ; LINES ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; CUTTING EDGE ; DENDRITIC CELLS ; CELL-LINES ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; MOUSE ; PATTERNS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; B-CELLS ; NATURAL-KILLER-CELLS ; NK cells ; cell lines ; REGULATOR ; NEUTROPHILS ; signaling ; RE ; PRODUCTS ; INTERFERENCE ; RNA INTERFERENCE ; LEADS ; CYTOKINE PRODUCTION ; LEVEL ; SIGNALS ; B-CELL ; immunology ; DAP12 ; AMPLIFIES INFLAMMATION ; PHOSPHOLIPASE C-GAMMA-1
    Abstract: The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-alpha and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12). In general, ITAM-mediated signals lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in mouse macrophages and dendritic cells. To date, signals downstream of the TREM-1 and DAP12 complex in myeloid cells are poorly defined. By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes. Using RNA interference to decrease the expression levels of NTAL, we demonstrate that in NTAL knockdown cell lines the phosphorylation of ERK1/2 is enhanced. In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca2+ after TREM-1 triggering. Most importantly, we demonstrate that NTAL acts as a negative regulator of TNF-alpha and IL-8 production after stimulation via TREM-1. Our results show that activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL, identifying NTAL as gatekeeper of TREM-1/DAP12-induced signaling in myeloid cells. The Journal of Immunology, 2007, 178: 1991-1999
    Type of Publication: Journal article published
    PubMed ID: 17277102
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  • 3
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; TISSUE ; TUMORS ; ACCUMULATION ; MICE ; TIME ; PATIENT ; LIGAND ; IFN-GAMMA ; prognosis ; DENDRITIC CELLS ; NUMBER ; LIGANDS ; CANCER-PATIENTS ; PROGNOSTIC-SIGNIFICANCE ; STRATEGIES ; IMMUNE-RESPONSE ; REJECTION ; CANCER PATIENTS ; chemokine ; ONCOLOGY ; RE ; CAPACITY ; THERAPIES ; TUMOR TISSUE ; REGULATORY T-CELLS ; LEVEL ; USA ; survival time ; cancer research ; ANTITUMOR RESPONSES ; NATURAL-KILLER-CELL ; ECTOPIC EXPRESSION ; natural killer ; NK-CELLS ; CHEMOKINE FAMILY
    Abstract: Several studies have correlated high numbers of tumor-infiltrating natural killer (NK) cells with a good prognosis for cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the tumors in IFN-gamma receptor knockout (IFN-gamma R-/-) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of lFN-gamma in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27(high) NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the tumor tissue. Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the tumor was severely impaired. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell-dependent survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors. Exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. [Cancer Res 2008;68(20):8437-45]
    Type of Publication: Journal article published
    PubMed ID: 18922917
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  • 4
    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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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; human ; INHIBITION ; VITRO ; cell line ; MOLECULES ; ACTIVATION ; LIGAND ; MACROPHAGES ; FAMILY ; DOMAIN ; BIOLOGY ; MEMBER ; MOLECULAR-BIOLOGY ; treatment ; MOLECULE ; antibodies ; antibody ; IDENTIFICATION ; CELL-LINE ; LINE ; LIGANDS ; NATURAL-KILLER-CELLS ; RECRUITMENT ; DE-NOVO ; CYTOTOXICITY ; signaling ; molecular biology ; molecular ; FAMILIES ; MOTIF ; HOMOLOGY ; USA ; function ; PHOSPHATASE ; NATURAL-KILLER ; immune cells ; IMMUNOGLOBULIN-LIKE RECEPTORS ; LECTIN-LIKE RECEPTOR
    Abstract: Activation of immune cells has to be tightly controlled to prevent detrimental hyperactivation. In this regulatory process molecules of the C-type lectin-like family play a central role. Here we describe a new member of this family, CLEC12B. The extracellular domain of CLEC12B shows considerable homology to the activating natural killer cell receptor NKG2D, but unlike NKG2D, CLEC12B contains an immunoreceptor tyrosine-based inhibition motif in its intracellular domain. Despite the homology, CLEC12B does not appear to bind NKG2D ligands and therefore does not represent the inhibitory counterpart of NKG2D. However, CLEC12B has the ability to counteract NKG2D-mediated signaling, and we show that this function is dependent on the immunoreceptor tyrosine-based inhibition motif and the recruitment of the phosphatases SHP-1 and SHP-2. Using monoclonal anti-CLEC12B antibodies we found de novo expression of this receptor on in vitro generated human macrophages and on the human myelo-monocytic cell line U937 upon phorbol 12-myristate 13-acetate treatment, suggesting that this receptor plays a role in myeloid cell function
    Type of Publication: Journal article published
    PubMed ID: 17562706
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  • 6
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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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  • 7
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; TUMORS ; LIGAND ; RESPONSES ; CUTTING EDGE ; MACROPHAGES ; MECHANISM ; DOWN-REGULATION ; SUSCEPTIBILITY ; IMMUNE-RESPONSES ; MOUSE ; CANCER-CELLS ; SURFACE ; MICA ; LIGANDS ; H60 ; NK cells ; NKG2D ; immune response ; IMMUNE-RESPONSE ; CELL-SURFACE ; regulation ; LYSIS ; USA ; immunology ; TUMOR-IMMUNITY
    Abstract: The NK cell-activating receptor NKG2D plays a prominent role in antitumor immune responses. Expression of the multiple NKG2D ligands must be tightly controlled to guarantee that NK cells attack tumors but not healthy cells. New data reveal a novel mechanism of posttranslational regulation of the mouse NKG2D ligand MULT1, in which MULT1 is ubiquitinated and degraded in healthy cells. In response to UV stress or heat shock, ubiquitination of MULT1 decreases and cell surface expression increases. Thus, targeting the ubiquitination machinery in cancer cells might increase the susceptibility of tumors to NK cell-mediated killing
    Type of Publication: Journal article published
    PubMed ID: 19204110
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  • 8
    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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  • 9
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; Germany ; human ; GENE ; HYBRIDIZATION ; TISSUE ; LINES ; PATIENT ; MARKER ; TISSUES ; ANTIGEN ; SKIN ; T cells ; T-CELLS ; CELL-LINES ; DOWN-REGULATION ; SIGNAL ; IN-SITU ; DESIGN ; MUTATION ; CELL-LINE ; LINE ; ABERRATIONS ; HETEROZYGOSITY ; MELANOMA ; REGION ; MUTATIONS ; MONOCLONAL-ANTIBODIES ; MHC CLASS-I ; PHENOTYPE ; IMMUNE ESCAPE ; TUMOR ESCAPE ; in situ hybridization ; MALIGNANT-CELLS ; RE ; LEVEL ; EVENTS ; LOSSES ; CD8(+) T cell ; B2M GENE ; MEDIATED LYSIS ; PROCESSING MACHINERY
    Abstract: Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8(+) T cells, is known to be caused by mutations in the beta 2-microglobulin (beta 2m) gene. We asked whether abnormalities of chromosome 15, harboring the beta 2m gene on 15q21, in addition to beta 2m gene mutations, are causative for the HILA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the beta 2m-negative metastatic melanoma tissues of four different patients and analyzed them for beta 2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the beta 2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) beta 2m gene mutations
    Type of Publication: Journal article published
    PubMed ID: 16740750
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  • 10
    Keywords: RECEPTOR ; CANCER ; CELLS ; IN-VITRO ; BLOOD ; CELL ; Germany ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; MICE ; PATIENT ; ACTIVATION ; LIGAND ; RESPONSES ; CUTTING EDGE ; IFN-GAMMA ; IMPACT ; CD8(+) T-CELLS ; T cell ; T-CELL ; LYMPHOMA ; DESIGN ; NATURAL-KILLER-CELLS ; NK cells ; CANCER-PATIENTS ; immune response ; IMMUNE-RESPONSE ; REVEALS ; CANCER PATIENTS ; ANTITUMOR IMMUNITY ; HUMAN DENDRITIC CELLS ; RE ; THERAPIES ; T-CELL-ACTIVATION ; interaction ; SUPPRESSOR ; USA ; TUMOR-BEARING MICE ; NKG2D RECEPTOR ; NOV ; response ; NATURAL-KILLER-CELL ; Myeloid cell ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; SUPPRESSES ; KILLER-CELLS ; natural killer ; NK-CELLS ; NK CELL ACTIVATION ; ACTIVATING RECEPTOR ; IMMUNE DYSFUNCTION
    Abstract: Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice and potently suppress T-cell activation. In this study, we investigated whether MDSCs regulate natural killer (NK)-cell function. We discovered that mononuclear Gr-1(+)CD11b(+)F4/80(+) MDSCs isolated from RMA-S tumor-bearing mice do not suppress, but activate NK cells to produce high amounts of IFN-gamma. Gr-1(+)CD11b(+)F4/80(+) MDSCs isolated from tumor-bearing mice, but not myeloid cells from naive mice, expressed the ligand for the activating receptor NKG2D, RAE-1. NK-cell activation by MDSCs depended partially on the interaction of NKG2D on NK cells with RAE-1 on MDSCs. NK cells eliminated Gr-1(+)CD11b(+)F4/80(+) MDSCs in vitro and upon adoptive transfer in vivo. Finally, depletion of Gr-1(+) cells that comprise MDSCs confirmed their protective role against the NK-sensitive RMA-S lymphoma in vivo. Our study reveals that MDSCs do not suppress all aspects of antitumor immune responses and defines a novel, unexpected activating role of MDSCs on NK cells. Thus, our results have great impact on the design of immune therapies against cancer aiming at the manipulation of MDSCs. (Blood. 2008; 112: 4080-4089)
    Type of Publication: Journal article published
    PubMed ID: 18753637
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