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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 30 December 2014, Vol.111(52), pp.E5688-96
    Description: Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.
    Keywords: Nk-Cell Licensing ; Nk–DC Interactions ; Tnfsf14 ; Natural Killer Cells ; Tumor Immunity ; Immunologic Surveillance ; Lymphocyte Activation ; Cell Communication -- Immunology ; Dendritic Cells -- Immunology ; Killer Cells, Natural -- Immunology ; Tumor Necrosis Factor Ligand Superfamily Member 14 -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Annals of the Rheumatic Diseases, March, 2014, Vol.73(3), p.A22(1)
    Keywords: Transcription Factors -- Research ; Transcription Factors -- Physiological Aspects ; Rheumatoid Arthritis -- Risk Factors ; Rheumatoid Arthritis -- Research ; Rheumatoid Arthritis -- Genetic Aspects ; Immune Response -- Research
    ISSN: 0003-4967
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e22842
    Description: Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-β. Release from TGF-β-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-β dependent manner following chronic contact-dependent interactions with tumour cells in vitro . In vivo , NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-β dependent inhibition upon autologous NK cells ex vivo . TGF-β antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-β treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-β blockade and both anti-TGF-β antibodies and a small molecule inhibitor of TGF-β signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-β blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.
    Keywords: Research Article ; Biology ; Medicine ; Genetics And Genomics ; Immunology ; Physiology ; Oncology ; Developmental Biology
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Annals of the Rheumatic Diseases March 2014, Vol.73(Suppl 1), p.A22
    Description: Rheumatoid arthritis (RA) is a polygenic disorder usually arising from combined genetic predisposition and environmental influences with associated dysfunctional immune responses. The X-box binding protein 1 (XBP1) transcription factor is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes including RA. XBP1 can also be activated in direct response to Toll-like Receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Our aim was to investigate the relevance of interactions between UPR and TLR signalling pathways in the serum and synovial fibroblasts (SFs) of patients with RA, using samples from healthy individuals and patients with osteoarthritis (OA) as controls
    ISSN: 0003-4967
    ISSN: 00034967
    E-ISSN: 1468-2060
    E-ISSN: 14682060
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  • 5
    Language: English
    In: The Biochemical journal, 01 November 2010, Vol.431(3), pp.423-31
    Description: Cytotoxic lymphocytes eliminate infected cells and tumours via the perforin-mediated delivery of pro-apoptotic serine proteases known as granzymes. Granzyme B triggers apoptosis via the cleavage of a repertoire of cellular proteins, leading to caspase activation and mitochondrial depolarization. A simple bioinformatics strategy identified a candidate granzyme B cleavage site in the widely expressed BNIP-2 (BCL2/adenovirus E1B-19K protein-interacting protein 2). Granzyme B cleaved recombinant BNIP-2 in vitro and endogenous BNIP-2 was cleaved during the NK (natural killer) cell-mediated killing of tumour cells. Cleavage required the site identified in the bioinformatics screen and was caspase-independent. Expression of either full-length BNIP-2 or a truncated molecule mimicking the granzyme B cleaved form was pro-apoptotic and led to the caspase-dependent cleavage of BNIP-2 at a site distinct from granzyme B cleavage. Inhibition of BNIP-2 expression did not affect the susceptibility to NK cell-mediated killing. Furthermore, target cells in which BID (BH3-interacting domain death agonist) expression was inhibited also remained highly susceptible to NK cell-mediated killing, revealing redundancy in the pro-apoptotic response to human cytotoxic lymphocytes. Such redundancy reduces the opportunity for escape from apoptosis induction and maximizes the chances of immune-mediated clearance of infected cells or tumour cells.
    Keywords: Cytotoxicity, Immunologic ; Carrier Proteins -- Metabolism ; Granzymes -- Metabolism ; Killer Cells, Natural -- Immunology
    ISSN: 02646021
    E-ISSN: 1470-8728
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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 November 2010, Vol.16(21), pp.5312-9
    Description: This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC.
    Keywords: Carcinoma, Renal Cell -- Drug Therapy ; Interleukins -- Administration & Dosage ; Kidney Neoplasms -- Drug Therapy ; Melanoma -- Drug Therapy ; Skin Neoplasms -- Drug Therapy
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    Language: English
    In: The Journal of Allergy and Clinical Immunology, March 2016, Vol.137(3), pp.955-957.e8
    Description: References1 Hum Mutat 27 2006 1041 1046 Interactive visual analysis of SNP data for rapid autozygosity mapping in consanguineous families Carr I.M. Flintoff K.J. Taylor G.R. Markham A.F. Bonthron D.T. 2 Am J Hum Genet 53 1993 252 263 Faster sequential genetic linkage computations Cottingham R.W. Idury R.M. Schäffer A.A. 3 Bioinformatics 25 2009 2078 2079 The sequence alignment/map format and SAMtools Li H. Handsaker B. Wysoker A. Fennell T. Ruan J. Homer N. 4 Genome Res 20 2010 1297 1303 The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. 5 Nat Genet 43 2011 491 498 A framework for variation discovery and genotyping using next-generation DNA sequencing data DePristo M.A. Banks E. Poplin R. Garimella K.V. Maguire J.R. Hartl C. 6 Nat Methods 7 2010 248 249 A method and server for predicting damaging missense mutations Adzhubei I.A. Schmidt S. Peshkin L. Ramensky V.E. Gerasimova A. Bork P. 7 Cell 135 2008 110 122 Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry Stathopulos P.B. Zheng L. Li G.-Y. Plevin M.J. Ikura M. 8 N Engl J Med 360 2009 1971 1980 STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity Picard C. McCarl C.-A. Papolos A. Khalil S. Lüthy K. Hivroz C. 9 J Exp Med 207 2010 2307 2312 Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma Byun M. Abhyankar A. Lelarge V. Plancoulaine S. Palanduz A. Telhan L. 10 J Immunol 188 2012 1523 1533 Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency Fuchs S. Rensing-Ehl A. Speckmann C. Bengsch B. Schmitt-Graeff A. Bondzio I. 11 J Dent Res 12 2014 94S 100S STIM1 and SLC24A4 are critical for enamel maturation Wang S. Choi M. Richardson A.S. Reid B.M. Seymen F. Yildirim M. 12 J Allergy Clin Immunol 136 2015 816 819.e4 A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency Schaballie H. Rodriguez R. Martin E. Moens L. Frans G. Lenoir C. 13 Am J Hum Genet 92 2013 271 278 Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy Böhm J. Chevessier F. Maues De Paula A. Koch C. Attarian S. Feger C. 14 Hum Mutat 35 2014 1221 1232 Gain-of-function mutation in STIM1 (P.R304W) is associated with stormorken syndrome Morin G. Bruechle N.O. Singh A.R. Knopp C. Jedraszak G. Elbracht M. 15 Mol Genet Metab 114 2015 474 482 York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1 Markello T. Chen D. Kwan J.Y. Horkayne-Szakaly I. Morrison A. Simakova O.
    Keywords: Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 8
    Language: English
    In: International Journal of Cancer, 15 May 2013, Vol.132(10), pp.2327-2338
    Description: Reovirus is a promising oncolytic virus, acting by both direct and immune‐mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus‐loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus‐treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon‐dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune‐mediated therapy against human colorectal or other cancers metastatic to the liver. What's new? Reovirus can deliver a double whammy to cancer: it hunts down and destroys ‐activated tumor cells, and it can also fire up the immune system against the tumor. The immune system, however, is a fickle ally; in addition to attacking tumor cells, an efficient immune response also rids the body of reovirus, hindering therapy. This study investigated whether therapeutic reovirus could be shielded from immune assault. They showed that loading reovirus onto blood mononuclear cells provides safe transportation to target cells, in this case, colorectal tumor cells, and the reovirus‐loaded immune cells themselves also launch an attack against tumor cells. Reovirus appears to be a promising new avenue for cancer treatment.
    Keywords: Reovirus ; Colorectal Liver Metastases ; Nk Cells ; Interferon‐Dependent
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
    Language: English
    In: Viruses, 03 January 2018, Vol.10(1)
    Description: It has been proposed that blood coagulation factors, principally factor X (FX), enhance the uptake of human adenovirus type 5 (Ad5) into cultured epithelial cells by bridging the viral hexon capsid protein and cell-surface heparan sulphate proteoglycans (HSPGs). We studied the effects of FX on Ad transduction of lymphoid cell lines (NK92MI, a natural killer cell line; Daudi, a B-cell line and Jurkat, a T-cell line) as well as primary peripheral blood lymphocytes (PBL) and HeLa epithelial cells using either replication-deficient Ad5, or a derivative in which the Ad5 fiber was replaced with that of another Ad type, Ad35, termed Ad5F35. PBL and NK92MI were resistant to Ad5 transduction. Transduction of Jurkat and Daudi cells by Ad5 was reduced by FX but without discernible effects on cell-surface Ad5 binding. FX reduced virus binding and transduction of all lymphoid cell lines by Ad5F35, as well as transduction of the T- and Natural Killer (NK)-cell populations of PBL. Flow cytometry analysis showed that all lymphoid cell lines were negative for HSPG components, in contrast to HeLa cells. FX reduced transduction of an HSPG-negative mutant Chinese hamster ovary cell line (CHOpgsA745) by Ad5 and Ad5F35, with Ad5F35 binding also being reduced by FX. These results point to fiber-dependent differences (Ad5 versus Ad35 fiber) in Ad binding to and transduction of human lymphoid and epithelial cells in the presence of FX.
    Keywords: Adenovirus ; Blood Lymphocytes ; Factor X ; Lymphoid Cells ; Virus Entry ; Virus Internalization ; Adenovirus Infections, Human -- Metabolism ; Adenoviruses, Human -- Physiology ; Factor X -- Metabolism ; Lymphocytes -- Metabolism
    E-ISSN: 1999-4915
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  • 10
    Language: English
    In: The Journal of clinical investigation, 01 May 2018, Vol.128(5), pp.2048-2063
    Description: Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin-mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.
    Keywords: Cancer Immunotherapy ; Expression Profiling ; Immunology ; Melanoma ; Oncology
    ISSN: 00219738
    E-ISSN: 1558-8238
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