Peter Brossart

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (171)1020.01 Total impact

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    ABSTRACT: Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14(+)HLA-DR(-/low) MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8(+) T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches.
    No preview · Article · Jan 2016 · Cancer Immunology and Immunotherapy

  • No preview · Article · Dec 2015 · Zeitschrift für Gastroenterologie
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    ABSTRACT: Purpose: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. Experimental design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. Results: In the training cohort (n=209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki67, p<0.001), Gleason score (p=0.004), and androgen receptor (AR) expression (p<0.001). Furthermore, PD-L1-positivity was prognostic for biochemical recurrence (BCR; p=0.004; HR=2.37 [95%CI=1.32-4.25]. In the test cohort (n=611) moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (p=0.011; HR=1.49 [95%CI=1.10-2.02]. The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (p<0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (p=0.007; HR=1.46 [95%CI=1.11-1.92]. Conclusion: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biological relevance in primary tumors. Further studies need to ascertain, if PD-1/PD-L1 targeted therapy might be a treatment option for hormone-naive prostate cancers.
    No preview · Article · Nov 2015 · Clinical Cancer Research
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    ABSTRACT: Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003–2005 we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients an intensified protocol consisting of i.d. injections (daily on days 0–3, 7–10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015 one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 months (all patients) and 89 months (favorable risk patients) exceeded predicted survival according to MSKCC risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 months. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than ten years.
    No preview · Article · Oct 2015 · OncoImmunology
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    ABSTRACT: Multiple myeloma (MM) is a clonal B cell malignancy characterized by proliferation of malignant plasma cells in the bone marrow. Despite high-dose melphalan therapy with autologous stem cell transplantation (ASCT) and the introduction of immunomodulatory drugs like bortezomib or lenalidomide, that have been associated with improved survival, MM is still incurable and new treatment options are needed. In B cell malignancies such as chronic lymphocytic leukaemia (CLL) or diffuse large B cell lymphoma (DLBCL), Syk (spleen tyrosine kinase) inhibitors have shown promising in vitro and first clinical results. In our study, we analyzed the potential of Syk as a target in MM. The MM cell lines AMO-1, U266 and RPMI8226 and primary MM cells were treated with the Syk inhibitors BAY61-3606, R406 or Piceatannol and proliferation, migration and apoptosis induction were analyzed. Effects on involved intracellular signaling cascades were determined by Western blotting. Furthermore, we analyzed synergistic and additive effects of Syk inhibitors in combination with established anti-myeloma drugs and experimental inhibitors (e.g. PI-3-Kinase inhibitor NVP-BEZ235). Incubation of MM cell lines as well as primary MM cells with Syk inhibitors resulted in a reduced proliferation and stromal cell-derived factor-1 alpha (SDF-1 alpha) induced migration that was accompanied by a concentration dependent inhibition of the MAP-Kinase, characterized by reduced phosphorylation of ERK an p38 molecules, and NF-kappaB signalling pathways. Furthermore, Syk inhibition induced apoptosis in MM cells in a dose-dependent manner, characterized by reduced expression of pro-caspase 3, increased PARP-1 cleavage and enhanced release of cytochrome c. In addition combined treatment of MM cells with Syk inhibitors and NVP-BEZ235 (dual PI3-kinase/mTOR inhibitor) or MAPK inhibitors (PD98059, SP600125, U0126, SB203580) resulted in increased apoptotic activity of the drugs. Our results show that Syk inhibition might represent a promising new treatment option in MM with an increased efficacy when combined with MAP kinase inhibitors. Furthermore, our study strongly underlines the potency of Syk inhibitors as a potential therapeutic treatment option for MM patients.
    Full-text · Article · Aug 2015
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    ABSTRACT: Despite considerable progress in recent years, the overall prognosis of metastatic malignant melanoma remains poor, and curative therapeutic options are lacking. Therefore, better understanding of molecular mechanisms underlying melanoma progression and metastasis, as well as identification of novel therapeutic targets that allow inhibition of metastatic spread, are urgently required. The current study provides evidence for aberrant cyclin-dependent kinase 5 (CDK5) activation in primary and metastatic melanoma lesions by overexpression of its activator protein CDK5R1/p35. Moreover, using melanoma in vitro model systems, shRNA-mediated inducible knockdown of CDK5 was found to cause marked inhibition of cell motility, invasiveness, and anchorage-independent growth, while at the same time net cell growth was not affected. In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases. Inhibition of lung metastasis was further validated in a syngenic murine melanoma model. CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype. Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells. Thus, experimental data presented here provide strong evidence for a crucial role of aberrantly activated CDK5 in melanoma progression and metastasis and establish CDK5 as promising target for therapeutic intervention. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · Aug 2015 · Translational oncology
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    ABSTRACT: Inhibitors of VEGF receptor (VEGFR) signaling such as sorafenib and sunitinib that are currently used in the treatment of malignant diseases have been shown to affect immunological responses by inhibition of the function of antigen presenting cells and T lymphocytes. The VEGFR-inhibitor axitinib has recently been approved for second line therapy of metastatic renal cell carcinoma. While there is some evidence that axitinib might interfere with the activation of T cells, not much is known about the effects of axitinib on dendritic cell (DC) phenotype and function. We here show that the addition of axitinib during the final Toll-like receptor-4-induced maturation step of monocyte-derived human DCs results in a reduced DC activation characterized by impaired expression of activation markers and co-stimulatory molecules such as CD80, CD83 and CD86. We further found a decreased secretion of interleukin-12 which was accompanied by reduced nuclear expression of the transcription factor cRel. In addition, we found a dose-dependent reduced activation of p38 and STAT3 in axitinib-exposed DCs, whereas the expression was not affected. The dysfunction of axitinib-exposed DCs was further underlined by their impaired induction of allogeneic T cell proliferation in a mixed lymphocyte reaction assay and inhibition of DC migration. Our results demonstrate that axitinib significantly affects DC differentiation and function primarily via the inhibition of the nuclear factor kappa B signaling pathway leading to impaired T cell activation. This will be of importance for the design of future vaccination protocols and therapeutic approaches aiming at combining different treatment strategies, eg such as programmed death-1 inhibitors with axitinib.
    No preview · Article · Jun 2015 · PLoS ONE
  • Annkristin Heine · Peter Brossart
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    ABSTRACT: In this issue of Blood, Schneidawind et al demonstrate that the adoptive transfer of CD4+ invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT).
    No preview · Article · May 2015 · Blood
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    ABSTRACT: Ruxolitinib is a small molecule inhibitor of the JAK kinases which has been approved for treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials also are being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer cells (NK cells) are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 24 MPN patients with or without ruxolitinib treatment and 28 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activitiy was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Apr 2015 · Cancer Research
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    ABSTRACT: Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT-signalling is known to be involved in the regulation of CD4(+) T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4(+) T cell responses, we undertook an in-depth analysis of CD4(+) T cell function upon ruxolitinib exposure. We observed a decrease in total CD3(+) cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro-inflammatory T-helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor-α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2-dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4(+) T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib-treated patients. © 2015 John Wiley & Sons Ltd.
    No preview · Article · Mar 2015 · British Journal of Haematology
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    ABSTRACT: Intensive therapy regimens in patients with acute myeloid leukemia (AML) frequently result in sepsis and septic shock. In this study, we investigated the prognostic outcome of AML patients requiring intensive care treatment due to severe sepsis or septic shock. We present a retrospective cohort study in a medical intensive care unit (ICU) of a university hospital that serves as a tertiary care center. Here we present data from 44 AML patients of our ICU with 29 requiring invasive mechanical ventilation due to sepsis and compared multiple clinical and laboratory parameters of ICU survivors and non-survivors. Mean age was 59.5 years, the overall mortality rate was 41 % (18/44), and the mortality rate among patients who received mechanical ventilation was 55 % (16/29). The mortality rate among younger patients (aged 60 years or less) was 17 % (3/18), while 58 % of the older patients died (15/26). The mortality rate among younger patients who received mechanical ventilation was 23 % (3/13) compared with 81 % (13/16) of the older patients. The mean invasive ventilation time was 415 h in non-survivors compared with 667 h in survivors. No differences could be identified between survivors and non-survivors, concerning multiple laboratory parameters or AML prognostic and therapeutic parameters; our analysis, however, confirmed a statistically significant difference in the patients' age. In previous studies, age was one of the most important prognostic factors in AML patients receiving mechanical ventilation due to severe sepsis or septic shock. In spite of improvements in diagnostic and treatment over the last couple of years, our study indicates that this fact still is true. However, the overall outcome has improved over the years due to improvements in intensive care medicine.
    No preview · Article · Mar 2015 · Journal of Cancer Research and Clinical Oncology
  • J. Rudolph · A. Heine · T. Quast · W. Kolanus · P. Brossart · D. Wolf

    No preview · Conference Paper · Mar 2015
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    ABSTRACT: Recent meta-analyses showed that antibiotic prophylaxis in patients with neutropenia after chemotherapy reduced the incidence of fever and mortality rate. Fluoroquinolones appear to be most effective and well tolerated. Thus, in April 2008, we changed our antibiotic prophylaxis regimen from cotrimoxazole/colistin (COT/COL) to the fluoroquinolone ciprofloxacin (CIP) in patients with acute myeloid leukemia (AML). The aim of this retrospective study was to compare efficacy and development of bacterial resistance with two different prophylaxis regimens over a time period of more than 4 years. Induction chemotherapy courses given for AML during the antibiotic prophylaxis period with COT/COL (01/2006-04/2008) and CIP (04/2008-06/2010) were retrospectively analyzed with a standard questionnaire. Eighty-five courses in the COT/COL group and 105 in the CIP group were analyzed. The incidence of fever was not significantly different (COT/COL 80 % vs CIP 77 %; p = 0.724). Also, the rate of microbiologically documented infections was nearly the same (29 vs 26 %; p = 0.625). In addition, there was no significant difference in the incidence of clinically documented infections (11 vs 19 %; p = 0.155) or in the rates of detected gram-positive and gram-negative bacteria. Of note, there was no increase in resistance rates or cases with Clostridium difficile-associated diarrhea in the CIP group. The antibiotic prophylaxis with CIP compared to COT/COL in AML was similarly effective with no increase in bacterial resistance. COT/COL may have the advantages of providing additional prophylaxis against Pneumocystis jirovecii pneumonia and leaving fluoroquinolones as an additional option for treatment of febrile neutropenia.
    No preview · Article · Jan 2015 · Supportive Care Cancer

  • No preview · Article · Jan 2015 · Zeitschrift für Gastroenterologie
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    ABSTRACT: We studied 1696 patients (18 to 61 years) with acute myeloid leukemia for ASXL1 mutations and identified these mutations in 103 (6.1%) patients. ASXL1 mutations were associated with older age (P<.0001), male sex (P=.041), secondary acute myeloid leukemia (P<.0001), and lower values for bone marrow (P<.0001) and circulating (P<.0001) blasts. ASXL1 mutations occurred in all cytogenetic risk-groups; normal karyotype (40%), other intermediate-risk cytogenetics (26%), high (24%) and low-risk (10%) cytogenetics. ASXL1 mutations were associated with RUNX1 (P<.0001) and IDH2R140 mutations (P=.007), whereas there was an inverse correlation with NPM1 (P<.0001), FLT3-ITD (P=.0002), and DNMT3A (P=.02) mutations. ASXL1 mutations were associated with lower complete remission rate (56% vs 74%; P=.0002), and both inferior event-free survival (at 5-years: 15.9% vs 29.0%; P=.02) and overall survival (at 5-years: 30.3% vs 45.7%; P=.0004) compared to wildtype ASXL1. In multivariable analyses, ASXL1 and RUNX1 mutation as single variable had no significant impact on prognosis. However, we observed a significant interaction (P=.04) for these mutations, in that patients with the genotype ASXL1mutated/RUNX1mutated had a higher risk of death (hazard ratio 1.8) compared to patients without this genotype. ASXL1 mutation, particularly in the context of a coexisting RUNX1 mutation, constitutes a strong adverse prognostic factor in acute myeloid leukemia. Copyright © 2015, Ferrata Storti Foundation.
    No preview · Article · Jan 2015 · Haematologica
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    ABSTRACT: Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase-3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated.
    Full-text · Article · Oct 2014 · PLoS ONE
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    ABSTRACT: The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITD), as well as concurrent gene mutations with regard to postremission therapy in 323 patients with FLT3-ITD positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (p=0.004) and IS in the tyrosine kinase domain 1 (TKD1, p=0.06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (CTX, n=121) or autologous hematopoietic stem cell transplantation (HSCT, n=17), an allelic ratio ≥0.51 was associated with an unfavorable relapse-free (RFS, p=0.0008) and overall survival (OS, p=0.004); after allogeneic HSCT (n=93), outcome was significantly improved in patients with a high allelic ratio (RFS, p=0.02; OS, p=0.03), whereas no benefit was seen in patients with low allelic ratio (RFS, p=0.38; OS, p=0.64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AML HD93, reference 29; AML HD98A, reference 30; AMLSG 07-04, identifier: NCT00151242.
    No preview · Article · Sep 2014 · Blood
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    ABSTRACT: Outcome of AML patients older than 60 years has remained poor due to unfavorable disease characteristics and patient-related factors. The randomized AMLSG 06-04 protocol was designed based on in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid (ATRA) with chemotherapy. Between 2004 and 2006, 186 patients were randomized to receive 2 induction cycles with idarubicin, cytarabine and ATRA with VPA (VPA) or without (STANDARD). In all patients consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared to STANDARD (40% vs. 52%; p=0.14) due to a higher early death rate (26% vs. 14%; p=0.06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the two arms (p=0.95 and p=0.57, respectively). However, relapse-free-survival was significantly superior in VPA compared to STANDARD (24.4% vs. 6.4% at 5 years, p=0.02). Explorative subset analyses revealed that AML with mutated NPM1 may particularly benefit from VPA. This study was registered at, identifier: NCT00151255.
    No preview · Article · May 2014 · Blood
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    ABSTRACT: Lenalidomide activates the immune system, but the exact immunomodulatory mechanisms of lenalidomide in vivo are poorly defined. In an observational study we assessed the impact of lenalidomide on different populations of immune cells in multiple myeloma patients. Lenalidomide therapy was associated with increased amounts of a CD8+ T cell subset, phenotypically staged between classical central memory T cells (TCM) and effector memory T cells (TEM), consequently termed TCM/TEM. The moderate expression of perforin/granzyme and phenotypic profile of these cells identifies them as not yet terminally differentiated, which makes them promising candidates for the anti-tumor response. In addition, lenalidomide-treated patients showed higher abundance of CD14+ myeloid cells co-expressing CD15. This population was able to inhibit both CD4+ and CD8+ T cell proliferation in vitro and could thus be defined as a yet undescribed novel myeloid-derived suppressor cell (MDSC) subtype. We observed a striking correlation between levels of TCM/TEM, mature Tregs and CD14+CD15+ MDSCs. In summary, lenalidomide induces both activating and inhibitory components of the immune system, indicating the existence of potential counter-regulatory mechanisms. These findings provide new insights into the immunomodulatory action of lenalidomide.
    No preview · Article · Apr 2014 · Clinical & Experimental Immunology
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    ABSTRACT: Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC.
    Full-text · Article · Apr 2014 · Translational oncology

Publication Stats

7k Citations
1,020.01 Total Impact Points


  • 2008-2015
    • University of Bonn
      • Institute of Pathology
      Bonn, North Rhine-Westphalia, Germany
  • 2009-2014
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 1999-2010
    • University of Tuebingen
      • • Division of Oncology, haematology, clinical immunology, rheumatology and pneumology
      • • Department of Internal Medicine
      Tübingen, Baden-Württemberg, Germany
  • 2005-2006
    • Universitätsklinikum Tübingen
      • Department of Medicine
      Tübingen, Baden-Württemberg, Germany
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy