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  • tumor  (10)
  • 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 ; 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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  • 3
    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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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; carcinoma ; PATHWAY ; GENE-EXPRESSION ; PROTEIN ; TRANSDUCTION ; ACTIVATION ; cervical cancer ; human papillomavirus ; ADHESION ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; NATURAL-KILLER-CELLS ; NK cells ; UTERINE CERVIX ; NF-kappa B ; IMMUNOLOGICAL SYNAPSE ; ONCOLOGY ; INTERCELLULAR-ADHESION MOLECULE-1 ; CERVICAL KERATINOCYTES ; CONJUGATION ; ICAM-1
    Abstract: NK cell recognition of tumor cells is mediated by a delicate balance of signals received by MHC class I-binding inhibitory NK cell receptors and activating NK cell receptors, which mainly bind to virus-, stress- or tumor-induced ligands. In addition, adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) and its receptors, the lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, are crucial for immune synapse formation and NK cell-mediated killing. In this study, we show that expression of the adhesion molecule ICAM-1 was rapidly induced by E6 and -E7 oncoproteins of HPV16, -18, -5 and -8, but not of HPV38 and -6 in primary human keratinocytes after retroviral transduction. ICAM-1 was upregulated in E6E7-expressing keratinocytes both at mRNA and protein levels. The observed ICAM-1 upregulation in HPV16-E6E7-expressing keratinocytes was partially dependent on activation of the NF-kappaB pathway. Importantly, the upregulated ICAM-1 expression in HPV16-E6E7-expressing keratinocytes led to enhanced conjugate formation with NK cells. We previously showed that HPV16-positive cervical carcinomas frequently express low levels of inhibitory NK cell ligands and high levels of activating NK cell ligands. Moreover, levels of the adhesion molecule ICAM-1 are enhanced by HPV16-E6/E7. Therefore, strategies that aim at harnessing NK cells might be beneficial for the treatment of cervical carcinoma.
    Type of Publication: Journal article published
    PubMed ID: 20473930
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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: 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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  • 7
    Keywords: tumor ; MONOCLONAL-ANTIBODY ; MICE ; RECOGNITION ; BETA-CELLS ; MELLITUS ; NK-CELLS ; VIRUS-INFECTED CELLS ; CYTOTOXICITY RECEPTOR NKP44 ; STREPTOZOTOCIN
    Abstract: Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.
    Type of Publication: Journal article published
    PubMed ID: 25719382
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  • 8
    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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  • 9
    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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  • 10
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; PROTEIN ; MOLECULES ; TUMORS ; LINES ; MICE ; LIGAND ; CUTTING EDGE ; IFN-GAMMA ; MECHANISM ; DENDRITIC CELLS ; mechanisms ; T cells ; T-CELL ; BINDING ; CELL-LINES ; DOWN-REGULATION ; SIGNAL ; HUMANS ; MELANOMA ; DELTA T-CELLS ; NK cells ; NKG2D ; INVOLVEMENT ; CD8(+) ; melanoma cells ; CELL-SURFACE ; cell lines ; INTERFERON-GAMMA ; GENE-MUTATIONS ; CYTOTOXICITY ; STAT1 ; BINDING PROTEIN ; CYTOKINE ; GLIOMA ; therapeutic ; CYTOMEGALOVIRUS UL16 GLYCOPROTEIN ; INTRACELLULAR RETENTION ; natural killer cell ; MHC class I loss ; TUMOR SURVEILLANCE
    Abstract: NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alpha p 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. (C) 2008 Wiley-Liss. Inc
    Type of Publication: Journal article published
    PubMed ID: 19089914
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