Adelheid Cerwenka

German Cancer Research Center, Heidelburg, Baden-Württemberg, Germany

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Publications (67)465.01 Total impact

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    ABSTRACT: Introduction: The role of CD3-CD56+ natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. Recently, it has been shown that peripheral blood NK cells can kill renal microvascular endothelial cells, suggesting a pathogenic role of NK cells in this disease. So far, subset distribution, phenotype, and function of peripheral blood NK cells in relation to GPA disease activity have not been elucidated. Moreover, it is not known whether NK cells infiltrate GPA tissue lesions. Methods: Paraffin sections of GPA granulomas and controls were stained with anti-CD56 and anti-CD3 antibodies. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. NK cell degranulation was analyzed using cocultures of patient PBMCs with target cells and surface expression of CD107a. Clinical data were extracted from medical records. Statistical analysis was performed in an exploratory way. Results: CD56+ cells were not detectable in active granulomatous GPA lesions but were found frequently in granulomas from tuberculosis and sarcoidosis patients. In GPA, the proportion of NK cells among peripheral blood lymphocytes correlated negatively with the Birmingham Vasculitis Activity Score (BVAS) (n = 28). Accordingly, NK cell percentages correlated positively with the duration of remission (n = 28) and were significantly higher in inactive GPA (BVAS = 0, n = 17) than in active GPA, healthy controls (n = 29), and inactive control diseases (n = 12). The highest NK cell percentages were found in patients with long-term remission and tapered immunosuppressive therapy. NK cell percentages >18.5 % of peripheral blood lymphocytes (n = 12/28) determined GPA inactivity with a specificity of 100 %. The differentiation into CD56(dim) and CD56(bright) NK cell subsets was unchanged in GPA (n = 28), irrespective of disease activity. Similar surface expression of the activating NK cell-receptors (NKp30, NKp46, and NKG2D) was determined. Like in healthy controls, GPA NK cells degranulated in the presence of NK cell receptor ligand bearing epithelial and lymphatic target cells. Conclusions: NK cells were not detectable in GPA granulomas. Peripheral blood NK cell percentages positively correlate with the suppression of GPA activity and could serve as a biomarker for GPA activity. Peripheral blood NK cells in GPA patients are mature NK cells with preserved immune recognition.
    Preview · Article · Dec 2015 · Arthritis Research & Therapy
  • Jens Pahl · Adelheid Cerwenka
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    ABSTRACT: Natural Killer (NK) cells are classically considered innate immune effector cells involved in the first line of defense against infected and malignant cells. More recently, NK cells have emerged to acquire properties of adaptive immunity in response to certain viral infections such as expansion of specific NK cell subsets and long-lasting virus-specific responses to secondary challenges. NK cells distinguish healthy cells from abnormal cells by measuring the net input of activating and inhibitory signals perceived from target cells through NK cell surface receptors. Acquisition of activating ligands in combination with reduced expression of MHC class I molecules on virus-infected and cancer cells activates NK cell cytotoxicity and release of immunostimulatory cytokines like IFN-γ. In the cancer microenvironment however, NK cells become functionally impaired by inhibitory factors produced by immunosuppressive immune cells and cancer cells. Here we review recent progress on the role of NK cells in cancer immunity. We describe regulatory factors of the tumor microenvironment on NK cell function which determine cancer cell destruction or escape from immune recognition. Finally, recent strategies that focus on exploiting NK cell anti-cancer responses for immunotherapeutic approaches are outlined. Copyright © 2015 Elsevier GmbH. All rights reserved.
    No preview · Article · Jul 2015 · Immunobiology
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    ABSTRACT: The S100A8/A9 heterodimer (calprotectin) acts as a danger signal when secreted into the extracellular space during inflammation and tissue damage. It promotes proinflammatory responses and drives tumor development in different models of inflammation-driven carcinogenesis. S100A8/A9 is strongly expressed in several human tumors, including hepatocellular carcinoma (HCC). Apart from this evidence, the role of calprotectin in hepatocyte transformation and tumor microenvironment is still unknown. The aim of this study was to define the function of S100A8/A9 in inflammation-driven HCC. Mice lacking S100a9 were crossed with the Mdr2-/- model, a prototype of inflammation-induced HCC formation. S100a9-/- Mdr2-/- (dKO) mice displayed no significant differences in tumor incidence or multiplicity compared to Mdr2-/- animals. Chronic liver inflammation, fibrosis and oval cell activation were not affected upon S100a9 deletion. Our data demonstrate that, although highly upregulated, calprotectin is dispensable in the onset and development of HCC, and in the maintenance of liver inflammation. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · May 2015 · International Journal of Cancer
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    Full-text · Poster · May 2015
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    ABSTRACT: 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. 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. 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. 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.
    Full-text · Article · May 2015 · BMC Cancer
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    ABSTRACT: Background aims Ex vivo expansion of natural killer (NK) cells is a strategy to produce large numbers of these effector cells for immunotherapy. However, the transfer of bench-top expansion protocols to clinically applicable methods is challenging for NK cell–based therapy because of regulatory aspects and scale-up issues. Therefore, we developed an automated, large-scale NK cell expansion process. Methods Enriched NK cells were expanded with interleukin-2 and irradiated clinical-grade Epstein-Barr virus–transformed lymphoblastoid feeder cells with the use of an automated system in comparison to manual expansion, and the cells were investigated for their functionality, phenotype and gene expression. Results Automated expansion resulted in a mean 850-fold expansion of NK cells by day 14, yielding 1.3 (±0.9) × 109 activated NK cells. Automatically and manually produced NK cells were comparable in target cell lysis, degranulation and production of interferon-γ and tumor necrosis factor-α and had similar high levels of antibody-dependent cellular cytotoxicity against rituximab-treated leukemic cells. NK cells after automated or manual expansion showed similar gene expression and marker profiles. However, expanded NK cells differed significantly from primary NK cells including upregulation of the functional relevant molecules TRAIL and FasL and NK cell–activating receptors NKp30, NKG2D and DNAM-1. Neither automatically nor manually expanded NK cells showed reduced telomere length indicative of a conserved proliferative potential. Conclusions We established an automated method to expand high numbers of clinical-grade NK cells with properties similar to their manually produced counterparts. This automated process represents a highly efficient tool to standardize NK cell processing for therapeutic applications.
    Full-text · Article · May 2015 · Cytotherapy
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    ABSTRACT: Background aims Ex vivo expansion of natural killer (NK) cells is a strategy to produce large numbers of these effector cells for immunotherapy. However, the transfer of bench-top expansion protocols to clinically applicable methods is challenging for NK cell–based therapy because of regulatory aspects and scale-up issues. Therefore, we developed an automated, large-scale NK cell expansion process. Methods Enriched NK cells were expanded with interleukin-2 and irradiated clinical-grade Epstein-Barr virus–transformed lymphoblastoid feeder cells with the use of an automated system in comparison to manual expansion, and the cells were investigated for their functionality, phenotype and gene expression. Results Automated expansion resulted in a mean 850-fold expansion of NK cells by day 14, yielding 1.3 (±0.9) × 109 activated NK cells. Automatically and manually produced NK cells were comparable in target cell lysis, degranulation and production of interferon-γ and tumor necrosis factor-α and had similar high levels of antibody-dependent cellular cytotoxicity against rituximab-treated leukemic cells. NK cells after automated or manual expansion showed similar gene expression and marker profiles. However, expanded NK cells differed significantly from primary NK cells including upregulation of the functional relevant molecules TRAIL and FasL and NK cell–activating receptors NKp30, NKG2D and DNAM-1. Neither automatically nor manually expanded NK cells showed reduced telomere length indicative of a conserved proliferative potential. Conclusions We established an automated method to expand high numbers of clinical-grade NK cells with properties similar to their manually produced counterparts. This automated process represents a highly efficient tool to standardize NK cell processing for therapeutic applications.
    Full-text · Article · May 2015 · Cytotherapy
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    Full-text · Dataset · Apr 2015
  • Alexander Steinle · Adelheid Cerwenka

    No preview · Article · Apr 2015 · Science
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    Dataset: JCI77440sd

    Full-text · Dataset · Mar 2015
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    Full-text · Dataset · Mar 2015
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    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.
    Full-text · Article · Feb 2015 · PLoS ONE
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    Oliver Hölsken · Matthias Miller · Adelheid Cerwenka
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    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.
    Preview · Article · Feb 2015 · Journal der Deutschen Dermatologischen Gesellschaft
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    Oliver Hölsken · Matthias Miller · Adelheid Cerwenka
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    ABSTRACT: ZusammenfassungIn den letzten Jahren hat die Immuntherapie wesentlichen Einfluss auf die klinische Therapie des malignen Melanoms gewonnen. Neben vielversprechenden T-Lymphozyten-basierten Ansätzen erhalten natürliche Killerzellen (NK-Zellen) zunehmende Aufmerksamkeit als Antitumor-Effektor-Zellen. HLA-Klasse-I-Moleküle inhibieren die Aktivierung von NK-Zellen, so dass diese präferentiell Tumorzellen angreifen, die HLA-Klasse-I-Moleküle in nur geringem Maß exprimieren. Der teilweise oder vollständige Verlust der HLA-Klasse-I-Expression ist ein häufiges Ereignis bei der Melanomentstehung. Gleichzeitig werden bei der malignen Transformation NK-Zell-Rezeptor-aktivierende Liganden induziert. Daher werden Melanomzellen durch NK-Zellen zumindest in vitro erkannt und lysiert. In vivo haben Melanome jedoch umfassende Strategien entwickelt, um dem durch NK-Zellen vermittelten Angriff zu entgehen. Eine Vielzahl neuartiger Ansätze zielt darauf ab, NK-Zellen zu nutzen, um Melanompatienten wirksam zu therapieren und den bestehenden “Escape-Mechanismen” der Tumorzellen entgegenzuwirken. Dieser Übersichtsartikel fasst die aktuellen Fortschritte auf diesem Gebiet zusammen.
    Preview · Article · Jan 2015 · Journal der Deutschen Dermatologischen Gesellschaft
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    ABSTRACT: Neuroinflammation plays a key role in secondary brain damage after stroke. Although deleterious effects of proinflammatory cytokines are well characterized, direct cytotoxic effects of invading immune cells on the ischemic brain and the importance of their antigen-dependent activation are essentially unknown. Here we examined the effects of adaptive and innate immune cells-cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells-that share the direct perforin-mediated cytotoxic pathway on outcome after cerebral ischemia in mice. Although CTLs and NK cells both invaded the ischemic brain, only brain-infiltrating CTLs but not NK cells were more activated than their splenic counterparts. Depletion of CTLs decreased infarct volumes and behavioral deficit in two ischemia models, whereas NK cell depletion had no effect. Correspondingly, adoptive CTL transfer from wild-type into Rag1 knock-out mice increased infarct size. Adoptive CTL transfer from perforin knock-out or interferon-γ knock-out mice into Rag1 knock-out mice revealed that CTL neurotoxicity was mediated by perforin. Accordingly, CTLs isolated from wild-type or interferon-γ knock-out but not from perforin knock-out mice induced neuronal cell death in vitro. CTLs derived from ovalbumin-specific T-cell receptor transgenic mice were not activated and infiltrated less into the ischemic brain compared with wild-type CTLs. Their transfer did not increase the infarct size of Rag1 knock-out mice, indicating antigen-dependent activation as an essential component of CTL neurotoxicity. Our findings underscore the importance of antigen-dependent, direct cytotoxic immune responses in stroke and suggest modulation of CTLs and their effector pathways as a potential new strategy for stroke therapy. Copyright © 2014 the authors 0270-6474/14/3416784-12$15.00/0.
    Full-text · Article · Dec 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Human cytomegalovirus (HCMV) infection is the most common cause of congenital viral infections and a major source of morbidity and mortality after organ transplantation. NK cells are pivotal effector cells in the innate defense against CMV. Recently, hallmarks of adaptive responses, such as memory-like features, have been recognized in NK cells. HCMV infection elicits the expansion of an NK cell subset carrying an activating receptor heterodimer, comprising CD94 and NKG2C (CD94/ NKG2C), a response that resembles the clonal expansion of adaptive immune cells. Here, we determined that expansion of this NKG2C+ subset and general NK cell recovery rely on signals derived from CD14+ monocytes. In a coculture system, a subset of CD14+ cells with inflammatory monocyte features produced IL-12 in response to HCMV-infected fibroblasts, and neutralization of IL-12 in this model substantially reduced CD25 upregulation and NKG2C+ subset expansion. Finally, blockade of CD94/NKG2C on NK cells or silencing of the cognate ligand HLA-E in infected fibroblasts greatly impaired expansion of NKG2C+ NK cells. Together, our results reveal that IL-12, CD14+ cells, and the CD94/NKG2C/HLA-E axis are critical for the expansion of NKG2C+ NK cells in response to HCMV infection. Moreover, strategies targeting the NKG2C+ NK cell subset have the potential to be exploited in NK cell–based intervention strategies against viral infections and cancer.
    Full-text · Article · Nov 2014 · The Journal of clinical investigation
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    Full-text · Dataset · Nov 2014
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    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 ADAM-10 and ADAM-17, as demonstrated through the use of pharmacological 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 malignant melanoma patients, compared to 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.
    Preview · Article · Apr 2014 · Cancer Research
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    ABSTRACT: NK cells express an array of activating and inhibitory receptors that determine NK cell responses upon triggering by cognate ligands. Although activating NK cell receptors recognize mainly ligands expressed by stressed, virus-infected, or transformed cells, most inhibitory receptors engage MHC class I, preventing NK cell activation in response to healthy cells. In this study, we provide insight into the regulation and function of additional receptors involved in mouse NK cell responses: CTLA-4 and CD28. CTLA-4 and CD28 engage the same ligands, B7-1 and B7-2, which are primarily expressed by APCs, such as dendritic cells. Our data demonstrate that activation of mouse NK cells with IL-2 induces the expression of CTLA-4 and upregulates CD28. CTLA-4 expression in IL-2-expanded NK cells was further up- or downregulated by IL-12 or TGF-β, respectively. Using gene-deficient NK cells, we show that CD28 induces, and CTLA-4 inhibits, IFN-γ release by NK cells upon engagement by the recombinant ligand, B7-1, or upon coculture with mature dendritic cells. Notably, we show that mouse NK cells infiltrating solid tumors express CD28 and CTLA-4 and respond to stimulation with recombinant B7-1, suggesting that the NK cell responses mediated by the CD28/CTLA-4:B7-1/B7-2 system could be of importance during malignant disease. Accordingly, our study might have implications for immunotherapy of cancer based on blocking anti-CTLA-4 mAbs.
    Full-text · Article · Mar 2014 · The Journal of Immunology
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    Evelyn Ullrich · Joachim Koch · Adelheid Cerwenka · Alexander Steinle
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    ABSTRACT: The activating immunoreceptor NKG2D endows cytotoxic lymphocytes with the capacity to recognize and eliminate infected or malignant cells. The recognition of such harmful cells is enabled by binding of NKG2D to various MHC class I-related glycoproteins, which are upregulated in the course of viral infection or malignant transformation. The past years have witnessed substantial progress in our understanding of the mechanisms underlying the regulation of NKG2D ligands (NKG2DLs) by malignant cells, of tumor-associated countermeasures promoting escape from NKG2D-dependent immunosurveillance, and of therapeutic measures that may bolster the NKG2D/NKG2DL system against malignancies. Here, we summarize the current knowledge on the NKG2D/NKG2DL system and outline opportunities to exploit the tumoricidal function of NKG2D for anticancer immunotherapy.
    Preview · Article · Oct 2013 · OncoImmunology

Publication Stats

4k Citations
465.01 Total Impact Points

Institutions

  • 2006-2015
    • German Cancer Research Center
      • Division of Genome Modifications and Carcinogenesis
      Heidelburg, Baden-Württemberg, Germany
    • CSU Mentor
      Long Beach, California, United States
  • 2011
    • Ben-Gurion University of the Negev
      • Department of Life Sciences
      Beersheba, Southern District, Israel
  • 2009
    • Heidelberg University
      • Institute of Immunology and Serology
      Heidelburg, Baden-Württemberg, Germany
  • 2000-2002
    • University of California, San Francisco
      • Department of Microbiology and Immunology
      San Francisco, California, United States
  • 2001
    • Karl-Franzens-Universität Graz
      • Institute of Psychology
      Gratz, Styria, Austria