Adelheid Cerwenka

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

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Publications (60)457.55 Total impact

  • 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.
    Immunobiology 07/2015; DOI:10.1016/j.imbio.2015.07.012 · 3.18 Impact Factor
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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.
    International Journal of Cancer 05/2015; 136(10). DOI:10.1002/ijc.29282 · 5.01 Impact Factor
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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.
    BMC Cancer 05/2015; 15(1):351. DOI:10.1186/s12885-015-1321-y · 3.32 Impact Factor
  • Alexander Steinle · Adelheid Cerwenka
    Science 04/2015; 348(6230):45-6. DOI:10.1126/science.aaa9842 · 31.48 Impact Factor
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    Dataset: JCI77440sd
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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.
    PLoS ONE 02/2015; 10(2):e0118936. DOI:10.1371/journal.pone.0118936 · 3.23 Impact Factor
  • 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.
    Journal der Deutschen Dermatologischen Gesellschaft 01/2015; 13(1). DOI:10.1111/ddg.12557 · 1.40 Impact Factor
  • 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.
    Journal der Deutschen Dermatologischen Gesellschaft 01/2015; 13(1). DOI:10.1111/ddg.12557_suppl · 1.40 Impact Factor
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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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2014; 34(50):16784-95. DOI:10.1523/JNEUROSCI.1867-14.2014 · 6.75 Impact Factor
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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.
    The Journal of clinical investigation 11/2014; 124(12). DOI:10.1172/JCI77440 · 13.77 Impact Factor
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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.
    Cancer Research 04/2014; 74(13). DOI:10.1158/0008-5472.CAN-13-3017 · 9.28 Impact Factor
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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.
    The Journal of Immunology 03/2014; 192(9). DOI:10.4049/jimmunol.1302091 · 5.36 Impact Factor
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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.
    OncoImmunology 10/2013; 2(10):e26097. DOI:10.4161/onci.26097 · 6.28 Impact Factor
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    Alexander Rölle · Julia Pollmann · Adelheid Cerwenka
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    ABSTRACT: Many previous reports on Natural Killer (NK) cells highlighted their ability to form the proverbial first line of defense against a variety of viral infections and malignancies. NK cells have been considered a part of innate immunity, characterized by invariant, germ-line encoded receptors for the recognition of pathogens and infected cells. In contrast, somatic rearrangement of receptor genes, the clonal expansion of antigen-specific cells, and the ability to mount a more potent memory response upon secondary challenge are traditionally considered hallmarks of T and B cells belonging to the adaptive immune system. More recently, exciting new data are challenging this conventional view [1]. A growing body of evidence indicates that under certain experimental conditions, NK cells share some of the features of adaptive immune cells. Progress in our understanding of how NK cells can exert functions resembling adaptive immune responses might have implications beyond conceptually questioning the classic division of the immune system into an innate and an adaptive branch and our general view of immunological memory. Novel insights on memory NK cells could also have a strong impact on the design of next generation vaccines against a variety of pathogens.
    PLoS Pathogens 09/2013; 9(9):e1003548. DOI:10.1371/journal.ppat.1003548 · 8.06 Impact Factor
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    ABSTRACT: Cytotoxic lymphocytes are important for immune responses against viral infections and cancer. They can kill target cells through the release of cytotoxic granules without themselves getting harmed in the process. Because the lysosomal associated membrane proteins (LAMPs) appear on the cell surface following cytotoxic granule exocytosis, we hypothesized that some of these proteins might be involved in transiently protecting cytotoxic lymphocytes from suicide. Intracellular expression of CD107a/LAMP-1, and to a lesser extent that of CD107b/LAMP-2, correlated with lymphocyte cytotoxic granule content. Engineered surface expression of CD107a/LAMP-1, but not of CD107b/LAMP-2, reduced the granule-mediated killing of transfected target cells. This was dependent on glycosylation of the CD107a/LAMP-1 hinge. Moreover, surface expression of CD107a/LAMP-1 reduced binding of perforin to cells. Importantly, knockdown of CD107a/LAMP-1 in primary human NK cells and deficiency of CD107a/LAMP-1 in mice resulted in increased NK cell apoptosis upon target cell-induced degranulation. Thus, our data support a novel role of CD107a/LAMP-1 in the protection of NK cells from degranulation-associated suicide, which may represent a general mechanism to transiently limit self-destruction by cytotoxic lymphocytes upon target cell killing.
    Blood 07/2013; 122(8). DOI:10.1182/blood-2012-07-441832 · 10.43 Impact Factor
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    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.
    Blood 06/2013; 122(5). DOI:10.1182/blood-2013-02-482513 · 10.43 Impact Factor
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    Jing Ni · Matthias Miller · Ana Stojanovic · Adelheid Cerwenka
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    ABSTRACT: The adoptive transfer of interleukin (IL)-2-expanded natural killer (NK) cells has provided unsatisfactory clinical benefits to patients affected by solid tumors. Our study demonstrates that the activation of NK cells with IL-12/IL-15/IL-18 prior to transfer into tumor-bearing mice is critical for obtaining high recovery rates, effector functions in vivo and tumor regression.
    OncoImmunology 04/2013; 2(4):e23811. DOI:10.4161/onci.23811 · 6.28 Impact Factor
  • Frank Momburg · Carsten Watzl · Adelheid Cerwenka
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    ABSTRACT: About 150 NK cell researchers met at the German Cancer Research Center (DKFZ) in Heidelberg, Germany from 26–28 September 2012 for the Natural Killer Cell Symposium which was organized by the NK cell study group of the German Society for Immunology (DGfI) and sponsored by the European Journal of Immunology (EJI), the European Federation of Immunological Societies (EFIS) and the DGfI. The meeting was a forum for the discussion of the function and regulation of these fascinating innate immune cells and the opportunities for the transfer of this knowledge to cancer immunotherapy.
    European Journal of Immunology 04/2013; 43(4). DOI:10.1002/eji.201370044 · 4.52 Impact Factor
  • Ana Stojanovic · Margareta P Correia · Adelheid Cerwenka
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    ABSTRACT: Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokine-producing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.
    Cancer Microenvironment 12/2012; 6(2). DOI:10.1007/s12307-012-0125-8

Publication Stats

3k Citations
457.55 Total Impact Points

Institutions

  • 2007–2015
    • German Cancer Research Center
      • Division of Genome Modifications and Carcinogenesis
      Heidelburg, Baden-Württemberg, Germany
  • 2011
    • Ben-Gurion University of the Negev
      • Department of Life Sciences
      Beersheba, Southern District, Israel
  • 2007–2009
    • Heidelberg University
      • Institute of Immunology and Serology
      Heidelburg, Baden-Württemberg, Germany
  • 2006
    • CSU Mentor
      Long Beach, California, United States
  • 2000–2002
    • University of California, San Francisco
      • Department of Microbiology and Immunology
      San Francisco, California, United States