TY - THES A1 - Schrama, David T1 - T-Zell-priming außerhalb sekundärer lymphatischer Gewebe T1 - T-cell priming outside of secondary lymphoid tissue N2 - T-Zellimmunantworten werden normalerweise durch folgenden Weg initiiert: unreife dendritische Zellen nehmen Antigen in der Peripherie auf, wandern in die sekundären lymphatischen Organe, wobei sie auf ihrem Weg sowohl reifen als auch das Antigen prozessieren. In den sekundären lymphatischen Organen angekommen, präsentieren sie als reife dendritische Zellen den T-Zellen die Antigene in Form von Peptiden zusammen mit kostimulierenden Molekülen. Dadurch rufen sie eine spezifische T-Zellantwort hervor. In der vorliegenden Arbeit wurde untersucht, ob nicht Situationen herbeigeführt werden können, die ein T-Zell priming außerhalb der sekundären lymphatischen Organe erlauben. Dazu wurden ein murines Modell, bei dem das Zytokin Lymphotoxin-alpha spezifisch am Tumor angereichert wurde, und ein humanes Modell, bei dem reife, antigenbeladene DC intradermal appliziert wurden, untersucht. Im murinen Modell zeigte sich, dass die gerichtete Anreicherung von Lymphotoxin-alpha am Tumor zu dessen Zerstörung führte, welche durch T-Zellen vermittelt wurde, und mit der Induktion eines tertiären lymphatischen Gewebes am Tumor assoziiert war. Dieses tertiäre lymphatische Gewebe war durch die Kompartimentalisierung von T- und B-Zellen und der Präsenz von high endothelial venules charakterisiert und besaß zudem mit dendritischen Zellen und naïven T-Zellen alle Voraussetzungen für ein in loco priming. Dementsprechend konnte in der Folge der gerichteten Lymphotoxin-alpa Therapie im Tumor ein Anstieg am T-Zellinfiltrat, welches sich oligoklonal zusammensetzte, beobachtet werden. In vitro Experimente verdeutlichte die Tumorspezifität der Therapie-induzierten T-Zellantwort, da die T-Zellen auf ein Tumorantigen mit der Ausschüttung von Interferon gamma reagierten und die Tumorzellen lysierten. Im humanen Modell wurden Hautbiopsien von Melanompatienten untersucht, denen im Rahmen einer klinischen Studie autologe, in vitro generierte und antigenbeladene DC intradermal appliziert wurden. Die Patienten erlaubten die Entnahme von Hautbiopsien aus den Injektionsstellen für wissenschaftliche Untersuchungen. Eine Induktion bzw. Verstärkung einer spezifischen T-Zellantwort durch die Vakzinierung mit antigenbeladenen dendritischen Zellen konnte bereits in zahlreichen Arbeiten und auch in dem in dieser Arbeit untersuchten Patientenkollektiv gezeigt werden. Bei der Analyse der Injektionsstellen zeigt sich, dass ein großer Teil der injizierten dendritischen Zellen in der Vakzinierungsstelle verharren und dass diese unabhängig von einer Beladung mit Antigen zu einer Induktion von high endothelial venules Charakteristika führte. Waren die dendritischen Zellen mit Antigen beladen, so führte dies zu einem stärkeren T-Zellinfiltrat in den Injektionsstellen, wobei sowohl naïve als auch central memory T-Zellen nachgewiesen wurde. Diese Zellen wurden vermutlich durch die Überexpression der DC CK1 und SDF1 Chemokinen in den Injektionsstellen, die chemotaktisch auf T-Zellen wirken, angezogen. Das Infiltrat in den Injektionsstellen war oligoklonal und wies tumorspezifische T-Zellen auf. Nachdem diese T-Zellklone im Blut der Patienten vor der Vakzinierung nicht nachweisbar waren, müssen sie zumindest in den Injektionsstellen expandiert sein. Interessanterweise konnte einer dieser Klone in Metastasen nachgewiesen werden, die nach der Vakzinierung dem Patienten entfernt wurden. In beiden Modellen wurde also durch die Manipulation des Mikromilieus, d.h. Lymphotoxin-alpa Anreicherung am Tumor bzw. Injektion von reifen dendritischen Zellen in die Haut, Strukturen wie z.B. high endothelial venules induziert, die ein in loco priming ermöglichen sollten. Dementsprechend riefen diese Veränderungen ein Tumorantigen-spezifisches Infiltrat hervor. Diese Ergebnisse deuten darauf hin, dass T-Zell priming auch außerhalb sekundärer lymphatischer Organe erfolgen kann. Prinzipiell scheint also nur der Kontakt von reifen, antigenbeladenen dendritischen Zellen mit den entsprechenden antigenspezifischen, naïven T-Zellen entscheiden zu sein. Die Möglichkeit des in vitro primings bekräftigt diese These. In vivo erfolgt dieses Aufeinandertreffen normalerweise in den sekundären lymphatischen Organen, doch konnte in der vorliegenden Arbeit gezeigt werden, dass Veränderungen des Mikromilieus diesen Kontakt auch in anderen Geweben ermöglicht. N2 - Cellular immune responses are initiated by direct interaction of naïve T cells with professional antigen presenting cells, i.e., dendritic cells. In general, this interaction takes place in secondary lymphoid organs: immature dendritic cells capture antigen in the periphery, and while homing to the secondary lymphoid organs they mature and process the antigen. In these organs they present peptides derived from the antigen together with co-stimulatory molecules to the naïve T cells and thereby initiate an antigen-specific T cell response. In the present work we tested if situations can be created allowing priming outside secondary lymphoid organs. To this end, a murine model in which lymphotoxin-alpha was specifically accumulated at the tumor site and a human model where in vitro generated, matured and antigen pulsed dendritic cells were injected intradermal into the patients were investigated. In the murine model the accumulation of lymphotoxin-alpha at the tumor site led to the eradication of the tumor. This therapeutic success was mediated by T cells and associated with the induction of a tertiary lymphoid tissue characterized by compartmentalized T and B cell aggregates and the presence of high endothelial venules. Moreover, with dendritic cells and naïve T cells present in these tissues requirements for in loco priming were fulfilled. Indeed, targeted lymphotoxin-alpha enlarged the T cell-infiltrate within the tumor. In vitro assays demonstrated the tumor-specificity of the therapy-induced infiltrate. In the human model skin biopsies taken from melanoma patients receiving dendritic cell based vaccination and participating at a clinical I study were investigated. The patients provided informed consent to participate in this experimental procedure and to donate skin biopsies for immunological monitoring. Skin biopsies were taken from the injection sites in which autologous, in vitro generated, maturated and antigen-pulsed dendritic cells were injected. Several reports including one about patients from the present patient cohort demonstrated the induction and/or enhancement of tumor specific T cell responses subsequent to dendritic cells based vaccination therapy. Our analysis demonstrated that most of the injected dendritic cells were entrenched at the injection site. The mere presence of mature dendritic cells in the skin caused the induction of high endothelial venules. In case the dendritic cells were pulsed with antigen the T cell infiltrate was enlarged and consisted both of naïve and central memory T cells. These cells were presumably attracted by the overexpression of the T cell attractant chemokines DC-CK1 and SDF-1 leading to an oligoclonal T cell infiltrate composed partially of tumor specific T cells. As T cell clones detected within the injections sites were not present among the peripheral blood lymphocytes, these clones were at least expanded in the injection sites. Notably, one clone could be detested in metastases of one patient excised after the vaccination. In both models manipulation of the microenvironment, i.e. targeting lymphotoxin-alpa to the tumor or injecting mature dendritic cells into the skin, respectively, induced structures like high endothelial venules which should enable in loco priming. Accordingly, these changes induced a tumor antigen specific T cell infiltrate. Thus, these results imply that T cells can be primed outside of secondary lymphoid tissues. Generally, the contact between mature, antigen presenting dendritic cells and the respective antigen specific T cells should be the only necessity for priming. Notably, the possibility of in vitro priming sustains this thesis. In vivo secondary lymphoid organs enable this contact. The present work, however, demonstrates that this contact can also take place in different tissue caused by manipulation of the respective microenvironment. KW - T-Lymphozyt KW - Priming KW - Melanom KW - Melanom KW - T-Zelle KW - priming KW - tertiäres lymphatisches Gewebe KW - Immunoconjugate KW - melanoma KW - T-cell KW - priming KW - tertiary lymphoid tissue KW - immunoconjugate Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-15060 ER - TY - JOUR A1 - Houben, Roland A1 - Hesbacher, Sonja A1 - Schmid, Corinna P. A1 - Kauczok, Claudia S. A1 - Flohr, Ulrike A1 - Haferkamp, Sebastian A1 - Müller, Cornelia S. L. A1 - Schrama, David A1 - Wischhusen, Jörg A1 - Becker, Jürgen C. T1 - High-Level Expression of Wild-Type p53 in Melanoma Cells is Frequently Associated with Inactivity in p53 Reporter Gene Assays N2 - Background: Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date. Methodology/Principal Findings: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5–8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53. Conclusions/Significance: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level. KW - Krebs KW - Hautkrebs Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69012 ER - TY - JOUR A1 - Becker, Jürgen C. A1 - Andersen, Mads H. A1 - Hofmeister-Müller, Valeska A1 - Wobser, Marion A1 - Frey, Lidia A1 - Sandig, Christiane A1 - Walter, Steffen A1 - Singh-Jasuja, Harpreet A1 - Kämpgen, Eckhart A1 - Opitz, Andreas A1 - Zapatka, Marc A1 - Bröcker, Eva-B. A1 - thor Straten, Per A1 - Schrama, David A1 - Ugurel, Selma T1 - Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma JF - Cancer Immunology, Immunotherapy N2 - Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. KW - peptide vaccination KW - therapy KW - survivin T-cell reactivity KW - melanoma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126215 VL - 61 IS - 11 ER - TY - JOUR A1 - Becker, Jürgen C. A1 - Andersen, Mads H. A1 - Hofmeister-Müller, Valeska A1 - Wobser, Marion A1 - Frey, Lidia A1 - Sandig, Christiane A1 - Walter, Steffen A1 - Singh-Jasuja, Harpreet A1 - Kämpgen, Eckhart A1 - Opitz, Andreas A1 - Zapatka, Marc A1 - Bröcker, Eva-B. A1 - thor Straten, Per A1 - Schrama, David A1 - Ugurel, Selma T1 - Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma JF - Cancer Immunology, Immunotherapy N2 - Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. KW - peptide vaccination KW - melanoma KW - survivin KW - T-cell reactivity KW - therapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124830 VL - 61 IS - 11 ER - TY - JOUR A1 - Alb, Miriam A1 - Sie, Christopher A1 - Adam, Christian A1 - Chen, Suzie A1 - Becker, Jürgen C. A1 - Schrama, David T1 - Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma JF - Cancer Immunology, Immunotherapy N2 - Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics. KW - regulatory T cell KW - melanoma KW - immune suppression KW - tumor-draining lymph node Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125096 VL - 61 IS - 12 ER - TY - JOUR A1 - Hafner, Christian A1 - Houben, Roland A1 - Baeurle, Anne A1 - Ritter, Cathrin A1 - Schrama, David A1 - Landthaler, Michael A1 - Becker, Jürgen C. T1 - Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma JF - PLoS One N2 - Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients. KW - rare KW - T-antigen KW - PIK3CA mutations KW - squamous cell KW - melanoma KW - polymavirus KW - cancer KW - tumors KW - akt KW - expression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131398 VL - 7 IS - 2 ER - TY - JOUR A1 - Schrama, David A1 - Ugurel, Selma A1 - Sucker, Antje A1 - Ritter, Cathrin A1 - Zapatka, Marc A1 - Schadendorf, Dirk A1 - Becker, Jürgen Christian T1 - STAT3 Single Nucleotide Polymorphism rs4796793 SNP Does Not Correlate with Response to Adjuvant IFNα Therapy in Stage III Melanoma Patients JF - Frontiers in Medicine N2 - Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients' progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients. KW - predictive marker KW - single nucleotide polymorphism KW - melanoma KW - interferon KW - STAT3 Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120602 SN - 2296-858X VL - 1 IS - 47 ER - TY - JOUR A1 - Adam, Christian A1 - Baeurle, Anne A1 - Brodsky, Jeffrey L. A1 - Schrama, David A1 - Wipf, Peter A1 - Becker, Jürgen Christian A1 - Houben, Roland T1 - The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma N2 - Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future. KW - apoptosis KW - cancer treatment KW - cell staining KW - cultured fibroplasts KW - heat shock response KW - membrans proteins KW - polymerase chain reaction Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112795 ER - TY - JOUR A1 - Hesbacher, Sonja A1 - Pfitzer, Lisa A1 - Wiedorfer, Katharina A1 - Angermeyer, Sabrina A1 - Borst, Andreas A1 - Haferkamp, Sebastian A1 - Scholz, Claus-Jürgen A1 - Wobser, Marion A1 - Schrama, David A1 - Houben, Roland T1 - RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells JF - Oncotarget N2 - The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells. KW - Merkel cell carcinoma KW - polyomavirus KW - Large T antigen KW - retinoblastoma protein KW - viral carcinogenesis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177858 VL - 7 IS - 22 ER - TY - JOUR A1 - Ritter, Cathrin A1 - Fan, Kaiji A1 - Paulson, Kelly G. A1 - Nghiem, Paul A1 - Schrama, David A1 - Becker, Jürgen C. T1 - Reversal of epigenetic silencing of MHC class I chain-related protein A and B improves immune recognition of Merkel cell carcinoma JF - Scientific Reports N2 - Merkel cell carcinoma (MCC) is a virally associated cancer characterized by its aggressive behavior and strong immunogenicity. Both viral infection and malignant transformation induce expression of MHC class I chain-related protein (MIC) A and B, which signal stress to cells of the immune system via Natural Killer group 2D (NKG2D) resulting in elimination of target cells. However, despite transformation and the continued presence of virally-encoded proteins, MICs are only expressed in a minority of MCC tumors in situ and are completely absent on MCC cell lines in vitro. This lack of MIC expression was due to epigenetic silencing via MIC promoter hypo-acetylation; indeed, MIC expression was re-induced by pharmacological inhibition of histone deacetylases (HDACs) both in vitro and in vivo. This re-induction of MICs rendered MCC cells more sensitive to immune-mediated lysis. Thus, epigenetic silencing of MICs is an important immune escape mechanism of MCCs. KW - epigenetic silencing KW - Merkel cell carcinoma KW - MHC class I chain-related protein KW - skin cancer Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167992 IS - 21678 ET - 6 ER -