المؤلفون: Tanja Fetter, Simon Fietz, Maya Bertlich, Christine Braegelmann, Luka de Vos-Hillebrand, Joerg Wenzel, Annkristin Heine, Jennifer Landsberg, Philipp Jansen

المصدر: Frontiers in Immunology, Vol 15 (2024)

مصطلحات موضوعية: autoimmune hemolytic anemia, melanoma, immunotherapy, anti-PD-1 antibody, anti-CTLA 4-antibody, immune-related adverse events, Immunologic diseases. Allergy, RC581-607

الوصف: IntroductionOver the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening.Case reportHerein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since.ConclusionHematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1342845/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/5b1358c322a14c438a32a1c798e8b362Test

المؤلفون: Simon Fietz, Anne Fröhlich, Cornelia Mauch, Luka de Vos-Hillebrand, Tanja Fetter, Jennifer Landsberg, Friederike Hoffmann, Judith Sirokay

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: case report, cutaneous squamous cell carcinoma, immunotherapy, anti-PD-1 antibody, cutaneous lupus erythematosus, Immunologic diseases. Allergy, RC581-607

الوصف: IntroductionThe anti-programmed cell death protein 1 (PD-1) antibody cemiplimab has shown promising results in the treatment of unresectable or metastatic squamous cell carcinoma, however, frequently leads to immune-related adverse events limiting therapy efficacy. Although cutaneous side effects are common, only very few cases of cutaneous lupus erythematosus have been reported under anti-PD-1 immunotherapy. So far, no case of cutaneous lupus has been described under treatment with cemiplimab.Case reportFor the first time, we report the case of a patient with advanced squamous cell carcinoma, who developed clinical and histological findings in sun-exposed skin that were consistent with anti-SS-A/Ro antibody-positive subacute cutaneous lupus erythematosus (SCLE) under treatment with cemiplimab. Additionally, laboratory chemical analyses revealed a severe immune-related hepatitis without clinical symptoms. Both, the SCLE and the hepatitis, resolved after the administration of topical and systemic steroids and the discontinuation of anti-PD-1 therapy.ConclusionTreatment with cemiplimab can be associated with the appearance of cutaneous lupus erythematosus in sun-exposed areas. Application of topical and systemic glucocorticoids can lead to a rapid resolution of the skin eruptions. Moreover, our case illustrates the possibility of simultaneously occurring severe immune-related adverse events. This highlights the importance of additional diagnostics to avoid overlooking additional immune-related adverse events.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1324231/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/5c65c93846d04e19a86da137502b47bdTest

المؤلفون: Niklas Klümper, Lennert Wüst, Jonas Saal, Damian J. Ralser, Romina Zarbl, Jonas Jarczyk, Johannes Breyer, Danijel Sikic, Bernd Wullich, Christian Bolenz, Florian Roghmann, Michael Hölzel, Manuel Ritter, Sebastian Strieth, Arndt Hartmann, Philipp Erben, Ralph M. Wirtz, Jennifer Landsberg, Dimo Dietrich, Markus Eckstein

المصدر: OncoImmunology, Vol 12, Iss 1 (2023)

مصطلحات موضوعية: biomarker, bladder cancer, CD274, DNA methylation, immune checkpoint blockade, immunotherapy, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: ABSTRACTPD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2162-402XTest

الوصول الحر: https://doaj.org/article/db84a83835784401bcaeca4a8df3487dTest

المؤلفون: Friederike Hoffmann, Alina Franzen, Luka de Vos, Lennert Wuest, Zsófi Kulcsár, Simon Fietz, Alexander Philippe Maas, Sarah Hollick, Marie Yatou Diop, Jennis Gabrielpillai, Timo Vogt, Pia Kuster, Romina Zarbl, Joern Dietrich, Glen Kristiansen, Peter Brossart, Jennifer Landsberg, Sebastian Strieth, Dimo Dietrich

المصدر: Clinical Epigenetics, Vol 15, Iss 1, Pp 1-13 (2023)

مصطلحات موضوعية: CTLA4, CTLA-4, Head and Neck Squamous Cell Carcinoma (HNSCC), DNA methylation, Biomarker, Immunotherapy, Medicine, Genetics, QH426-470

الوصف: Abstract Background The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. Methods We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. Results Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. Conclusions Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1868-7083Test

الوصول الحر: https://doaj.org/article/2828807dfb384e6996689ecfb93a477eTest

المؤلفون: Damian J. Ralser, Emmanuelle Herr, Luka de Vos, Zsófi Kulcsár, Romina Zarbl, Niklas Klümper, Gerrit H. Gielen, Alexander Philippe Maas, Friederike Hoffmann, Jörn Dietrich, Pia Kuster, Alexander Mustea, Nicole Glodde, Glen Kristiansen, Sebastian Strieth, Jennifer Landsberg, Dimo Dietrich

المصدر: Biomarker Research, Vol 11, Iss 1, Pp 1-17 (2023)

مصطلحات موضوعية: ICOS, ICOS DNA methylation, Epigenetics, Immune checkpoint blockade, Melanoma, Predictive biomarker, Therapeutics. Pharmacology, RM1-950

الوصف: Abstract Background Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation. Methods We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response. Results Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine. Conclusion Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2050-7771Test

الوصول الحر: https://doaj.org/article/e3bb36e51ff44e6f9b8d700fc99a8755Test

المؤلفون: Caterina Giraulo, Roberta Turiello, Lavinia Orlando, Sonia Leonardelli, Jennifer Landsberg, Raffaella Belvedere, Georg Rolshoven, Christa E. Müller, Michael Hölzel, Silvana Morello

المصدر: Biomedicine & Pharmacotherapy, Vol 165, Iss , Pp 115225- (2023)

مصطلحات موضوعية: CD73, Adenosine, Nutrient deprivation, TGF-β,Melanoma, Therapeutics. Pharmacology, RM1-950

الوصف: CD73 is the key enzyme in the generation of extracellular adenosine, a mediator involved in tumor progression, tumor immune escape and resistance to anti-cancer therapeutics. Microenvironmental conditions influence the expression of CD73 in tumor cells. However how CD73 expression and activity is regulated in a stress condition of lower nutrient availability are largely unknown. Our results indicate that serum starvation leads to a marked up-regulation of CD73 expression on A375 melanoma cells in a time-dependent manner. The cell-surface expression of CD73 is associated with an increased release of TGF-β1 by starved cells. Blockade of TGF-β1 receptors or TGFβ/SMAD3 signaling pathway significantly reduce the expression of CD73 induced by starvation. Treatment of cells with rTGF-β1 up-regulates the expression of CD73 in a concentration-dependent manner, confirming the role of this pathway in regulating CD73 in melanoma A375 cells. The increased expression of CD73 is associated with enhanced AMPase activity, which is selectively reduced by inhibitors of CD73 activity, APCP and PSB-12489. Pharmacological blockade of CD73 significantly inhibits invasion of melanoma cells in a transwell system. Furthermore, using multiplex immunofluorescence imaging we found that, within human melanoma metastases, tumor cells at the dedifferentiated stage show the highest CD73 protein expression. In summary, our data provide new insights into the mechanism regulating the expression/activity of CD73 in melanoma cells in a condition of lower availability of nutrients, which is a common feature of the tumor microenvironment. Within human metastatic melanoma tissues elevated protein expression of CD73 is associated with an invasive-like phenotype.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332223010168Test; https://doaj.org/toc/0753-3322Test

الوصول الحر: https://doaj.org/article/2d01d7fab2754c648cad5647ebf10af7Test

المؤلفون: Julian P. Layer, Katharina Layer, Gustavo R. Sarria, Fred Röhner, Cas S. Dejonckheere, Lea L. Friker, Thomas Zeyen, David Koch, Davide Scafa, Christina Leitzen, Mümtaz Köksal, Frederic Carsten Schmeel, Niklas Schäfer, Jennifer Landsberg, Michael Hölzel, Ulrich Herrlinger, Matthias Schneider, Frank A. Giordano, Leonard Christopher Schmeel

المصدر: Current Oncology, Vol 30, Iss 2, Pp 1300-1313 (2023)

مصطلحات موضوعية: FSRT, stereotactic radiotherapy, hypofractionation, brain metastases, radiation necrosis, toxicity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Purpose: To determine the safety and outcome profile of five-fraction stereotactic radiotherapy (FSRT) for brain metastases (BM), either as a definitive or adjuvant treatment. Methods: We assessed clinical data of patients receiving five fractions of 7 Gy each (cumulative physical dose of 35 Gy) to BM or surgical cavities. The primary endpoints were toxicity and radiation necrosis (RN) rates. Secondary endpoints were 1-year cumulative local control rate (LCR) and estimated overall survival (OS). Results: A total of 36 eligible patients receiving FSRT to a total of 49 targets were identified and included. The median follow up was 9 (1.1–56.2) months. The median age was 64.5 (34–92) years, the median ECOG score was 1, and the median Diagnostic-Specific Graded Prognostic Assessment (DS-GPA) score was 2. Treatment was well tolerated and there were no grade 3 adverse events or higher. The overall RN rate was 14.3% and the median time to RN was 12.9 (1.8–23.8) months. RN occurrence was associated with immunotherapy, young age (≤45 years), and large PTV. The cumulative 1-year local control rate was 83.1% and the estimated median local progression free-survival was 18.8 months. The estimated median overall survival was 11 (1.1–56.2) months and significantly superior in those patients presenting with RN. Conclusions: FSRT with 5 × 7 Gy represents a feasible, safe, and efficient fast track approach of intensified FSRT with acceptable LC and comparable RN rates for both the adjuvant and definitive RT settings.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1718-7729/30/2/101Test; https://doaj.org/toc/1198-0052Test; https://doaj.org/toc/1718-7729Test

الوصول الحر: https://doaj.org/article/14acb167281c4e949dff21e05e773afcTest

المؤلفون: Roman Rüdiger, Franziska Geiser, Manuel Ritter, Peter Brossart, Mignon-Denise Keyver-Paik, Andree Faridi, Hartmut Vatter, Friedrich Bootz, Jennifer Landsberg, Jörg C. Kalff, Ulrich Herrlinger, Glen Kristiansen, Torsten Pietsch, Stefan Aretz, Daniel Thomas, Lukas Radbruch, Franz-Josef Kramer, Christian P. Strassburg, Maria Gonzalez-Carmona, Dirk Skowasch, Markus Essler, Matthias Schmid, Jennifer Nadal, Nicole Ernstmann, Amit Sharma, Benjamin Funke, Ingo G. H. Schmidt-Wolf

المصدر: BMC Cancer, Vol 21, Iss 1, Pp 1-9 (2021)

مصطلحات موضوعية: Cancer, Migration background, Matched-pair analysis, Response rate, Survival, Socioeconomic status, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany. Methods Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002–December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression). Results Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar’s test, P = 0.346) between both collectives. Conclusion Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/4731b9fce47b41f2b9a7007a0942db2aTest

المؤلفون: Luka de Vos, Ingela Grünwald, Emma Grace Bawden, Jörn Dietrich, Kathrin Scheckenbach, Constanze Wiek, Romina Zarbl, Friedrich Bootz, Jennifer Landsberg, Dimo Dietrich

المصدر: Epigenetics, Vol 15, Iss 11, Pp 1195-1212 (2020)

مصطلحات موضوعية: cd28, cd80, cd86, ctla4, icos, dna methylation, immune checkpoint, hnscc, prognosis, tumour microenvironment, hpv, Genetics, QH426-470

الوصف: CTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of biomarkers for response prediction to anti-CTLA-4 immunotherapy. We investigated methylation of the encoding genes CD28, CTLA4, ICOS, CD80, and CD86 at single CpG resolution (51 CpG sites) in a cohort of HNSCC (N = 528) and normal adjacent tissue samples (N = 50) provided by The Cancer Genome Research Atlas, in isolated blood leukocytes from healthy individuals (N = 28), and HNSCC cell lines (N = 39). We analysed methylation levels with regard to mRNA expression, overall survival, mutational load, interferon-γ signature, and signatures of immune cell infiltrates. Depending on the location of the CpG sites (promoter, promoter flank, gene body, and intergenic sites), we found significant differences in methylation levels among isolated leukocytes, between leukocytes and HNSCC cell lines, and among HNSCCs. Methylation of all analysed genes correlated inversely or positively with mRNA expression, depending on the CpG site. CD28, CTLA4, and ICOS revealed almost identical correlation patterns. Furthermore, we found significant correlations with survival and features of response to immunotherapy, i.e. interferon-γ signature, signatures of tumour infiltrating immune cells, and mutational load. Our results suggest CD28, CTLA4, ICOS, CD80, and CD86 expression levels are epigenetically co-regulated by DNA methylation. This study provides rationale to test their DNA methylation as potential biomarker for prediction of response to CTLA-4 immune checkpoint inhibitors.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1559-2294Test; https://doaj.org/toc/1559-2308Test

الوصول الحر: https://doaj.org/article/57166499a8bc49da998576e00116f167Test

المؤلفون: Dennis Niebel, Judith Sirokay, Friederike Hoffmann, Anne Fröhlich, Thomas Bieber, Jennifer Landsberg

المصدر: Dermatology and Therapy, Vol 10, Iss 4, Pp 835-846 (2020)

مصطلحات موضوعية: Basal-cell carcinoma, Basal-cell carcinoma syndrome, Immunotherapy, Radiotherapy, Rodent ulcer, Smoothened receptor, Dermatology, RL1-803

الوصف: Abstract Treatment of choice for nodular basal-cell carcinomas (BCCs) is complete excision, implying that small lesions are of minor concern. Metastasis is very rare (

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2193-8210Test; https://doaj.org/toc/2190-9172Test

الوصول الحر: https://doaj.org/article/5257c0ee5e5246dabd7452bff1453cbfTest