Abstract
Background: Growth and differentiation factor 15 (GDF-15), a divergent member of the TGF-β protein superfamily, shows low physiological baseline expression. GDF-15 is, however, strongly ...upregulated during pregnancy. It is further induced in stressed and damaged tissues, where it limits immune infiltration and inflammation. In solid tumors, GDF-15 was shown to be a key inhibitor of T-cell infiltration. While this might already explain the strong correlation between GDF-15 overexpression and poor survival with or without checkpoint-based immunotherapy, effects of GDF-15 on dendritic cells and monocytes may further shape the tumor microenvironment.
Methods: To analyze the impact of GDF-15 in murine tumor models, GDF-15 was either deleted by CRISPR/CAS9 gene editing or neutralized by administration of a blocking antibody. Effects on tumor growth were recorded and the composition of the tumor microenvironment was characterized by flow cytometry. More detailed insight into tumor-immune interactions was obtained via the CrownBio Mouse I/O RNA-Seq Panel. Specific effects on polarization of innate and on antigen-specific priming of adaptive immune cells were confirmed in cellular assays in vitro.
Results: Tumor-derived GDF-15 modulates the tumor microenvironment by inhibiting infiltration and activation of myeloid cells. GDF-15 thereby impairs the induction of antitumoral immune responses. Deletion of GDF-15 enhances infiltration of innate cells into immune-excluded tumors, supports the priming of naïve T cells by dendritic cells and generates a pro-inflammatory tumor microenvironment. In vitro, GDF-15 inhibits DC maturation and synapse formation, thus preventing successful T-cell activation. Moreover, GDF-15 interferes with M1 polarization of macrophages.
Conclusion: GDF-15 secretion helps tumors to generate a microenvironment that is poorly infiltrated by immune cells. GDF-15 further polarizes myeloid cells towards a tumor-promoting, anti-inflammatory phenotype. By inducing a more pro-inflammatory tumor phenotype, anti-GDF-15 antibodies may synergize with other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474) is ongoing.
Citation Format: Markus Haake, Beatrice Haack, Sabrina Genßler, Julia Weigandt, Marlene Auer, Vincent Thiemann, Wahid M. Haq, Melanie Haag, Florian Wedekink, Birgitt Fischer, Kathrin Klar, Matthias Wölfl, Christine Schuberth-Wagner, Jorg Wischhusen. Tumor-derived GDF-15 promotes immune escape of tumors by functional alteration of the myeloid compartment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6118.
In lymphocytes, glucocorticoids (GC)- and interleukin-4-signaling pathways are known to interact, as evidenced by inhibition of IL-4-mediated proliferation by dexamethasone or suppression of ...GC-induced apoptosis by IL-4. In this study, we characterized the molecular basis for this reciprocal interference. We report that, in murine CTLL-2 cells, IL-4 inhibits GC-induced MMTV (mouse mammary tumor virus) promoter transactivation, and that GC suppress IL-4-induced transactivation of a STAT6 (signal transducers and activators of transcription 6)-responsive promoter without affecting IL-4-stimulated STAT6 DNA-binding. Moreover, we evidenced a physical association between GC receptor and STAT6, which proved to be functionally relevant, since STAT6 overexpression increased the IL-4 inhibitory effect on GC-induced MMTV transactivation.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Environmental pollutants can influence the expression of immunoregulatory molecules and, in this way, promote allergies. The local synthesis of proinflammatory chemokines is an important aspect in ...the development of allergic airway inflammation. We have characterized the influence of pyrene, a polycyclic aromatic hydrocarbon (PAH) contained, for example, in diesel exhaust particles (DEP), on transcription and secretion of the chemokines interleukin-8 (IL-8) and eotaxin. Reporter genes under control of the respective promoters were tested in the human cell lines A549 and HeLa, mRNA production was assayed in A549 cells and protein production was measured by ELISA in cell supernatants from primary human fibroblasts. Pyrene content of cell supernatants was measured by analytical HPLC. Promoter activity, mRNA production and protein expression of IL-8 were increased by pyrene. The activating effect in reporter gene studies was abolished by mutating either an NF-κB or an AP-1 binding site in the IL-8 promoter. In contrast, pyrene showed no effect on transcription from the eotaxin promoter, despite the important role of this chemokine in asthma. Our data show that pyrene has specific effects on chemokine synthesis, which are not restricted to mediators primarily associated with atopic diseases. Pyrene also affected cells not derived from lung tissue, which suggests a broader immunoregulatory influence for this pollutant.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Der Transkriptionsfaktor Stat6 vermittelt zentrale Wirkungen von IL-4 und IL-13, die in der Pathologie atopischer Erkrankungen eine Rolle spielen. Seine Spezifität für diese beiden ...allergieassoziierten Cytokine ist eine wesentliche Motivation ihn näher zu untersuchen. In dieser Arbeit sollte mehr über die Funktion von Stat6 herausgefunden werden. Außerdem wurden Möglichkeiten untersucht dieses Verhalten zu beinflussen. Einen Schwerpunkt der Arbeit bildete die Regulation des Eotaxin-1-Promotors. Eotaxin-1 ist einer der stärksten Rekrutierungsfaktoren für Eosinophile, die eine zentrale Rolle bei der Immunpathologie allergischer Erkrankungen spielen. Mit Hilfe der Daten konnte eine neue Hypothese zur Regulation des Eotaxin-1-Promotors entwickelt werden. Zum Vergleich wurde mit der Untersuchung des Promotors eines weiteren Chemokins, des MCP-4, begonnen. In Zusammenarbeit mit Dr. Sascha Stolzenberger wurde ein Weg untersucht den Stat6-Signalweg zu hemmen. Dabei wurden mit Hilfe des Antennapedia-Peptides Stat6-Bindepeptide in die Zelle transportiert, um dort über eine kompetitive Hemmung die Signaltransduktion zu unterbinden. Ergebnis dieser Arbeiten ist ein hochspezifischer, aber nur transient wirkender Stat6 Inhibitor. Die Stat6/DNA-Wechselwirkung wurde mit der Magnetobead-Technik untersucht. Dabei werden Promotorfragmente an Magnetkügelchen gekoppelt und unter Ausnutzung der Magnetisierung an die DNA bindende Proteine isoliert und über SDS-PAGE/Immunoblotanalyse untersucht. Mit dem Verfahren konnte die Stat6-Bindung an acht verschiedene Promotoren nachgewiesen werden. In Zusammenarbeit mit der Arbeitsgruppe Pallardy aus Paris wurde die Wechselwirkung von Stat6 mit dem Glucocorticoid-Rezeptor untersucht. Glucocorticoide kontrollieren Entzündungen und Interaktionen des aktivierten Rezeptors mit anderen Proteinen aus der Stat-Familie sind seit längerem bekannt. Wie in dieser Arbeit gezeigt wurde, interagiert Stat6 mit dem Glucocorticoidrezeptor unabhängig von einer Bindung an DNA. Zusätzlich wurde der Mucin-2-Promotor auf Stat6-Regulierung untersucht. Mucine sind wichtige Bestandteile des Schleimes. Verstärkte Schleim-Sekretion ist ein klinisches Symptom asthmatischer Erkrankungen und trägt zur Zerstörung der Lunge bei. Ein potentiell Stat6 reguliertes Fragment aus dem Mucinpromoter wurde mit Hilfe von PCR-Techniken isoliert und in Reportergenvektoren kloniert.
The transcriptionfactor Stat6 mediates central effects of the interleukins (IL)-4 and -13, that play important roles in the pathology of Allergy and Asthma. The specificity of these both Allergy-associated cytokines is a strong motivation to investigate the detailed functions of Stat6 and to search for possibilities to influence the behaviour of this transcriptionfactor. The main focus of this work was the regulation of the Eotaxin-1-promoter. The Eotaxin-1 chemokine is one of the most potent recruiting factors for eosinophils, that play a central role in the immunopathology of allergic diseases. On the basis of these data a new model for the regulation was created. In addition to this the investigation of another chemokine promoter, the MCP-4-promoter, was started. In another part of this work a specific Stat6-binding-peptide to inhibit the IL-4 signaltransduction pathway was established. Using the Antennapedia-carrier-peptide allowed to shuttle Stat6-binding peptides into cells where they prevented Stat6 mediated signalling by competitive inhibition. Thus the Stat6-binding-peptide came out to be a transient Stat6 inhibitor with high specificity. The Stat6/DNA-interaction was investigated by DNA-pull-down assays with magnetobeads. Fragments of different promoters are linked to magnetobeads and by using magnetic forces the DNA binding proteins are isolated. This application was used to show Stat6-binding to 8 different promoters. Another subject of this work was the interaction of Stat6 with the glucocorticoid receptor. It is well known that glucocorticoids control inflammation and that the activated receptor interacts with different proteins of the Stat-family. In collaboration with the group of Marc Pallardy in Paris we were able to show that Stat6 interacts with the glucocorticoid receptor independently of DNA binding. In association with Stat6 the regulation of the Mucin-2-promoter seemed to be an interesting aspect. Mucins are essential components of mucus (slime). Enhanced mucus-secretion is a symptom of asthmatic diseases and contributes to the destruction of the lung. A potentially Stat6 regulated fragment was isolated by PCR-techniques and cloned into reportergene vectors.
The transcription factor Stat6 (signal transducer and activator of transcription 6) is activated following stimulation with interleukin (IL)‐4 or IL‐13. Stat6 binds via a single SH2 domain first to ...tyrosine‐phosphorylated motifs in the IL‐4Rα chain, and then to another Stat6 molecule, which results in the formation of active dimers. We show here that a peptide derived from the Stat6‐binding region of IL‐4Rα (Stat6BP) is an effective inhibitor when it is delivered into cells by coupling with a membrane‐permeable peptide. Stat6BP completely inhibited IL‐4 dependent phosphorylation of Stat6, as well as basal and IL‐4 stimulated transcription from a reporter gene construct with a Stat6‐dependent promoter, while IL‐3 and IL‐4 dependent phosphorylation of Stat5 was not affected. The inhibitory effect of Stat6BP was transient, but could be prolonged by treating the cells with the phosphatase inhibitor pervanadate.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
This work aims at giving Trotter errors in digital quantum simulation (DQS) of collective spin systems an interpretation in terms of quantum chaos of the kicked top. In particular, for DQS ...of such systems, regular dynamics of the kicked top ensures convergence of the Trotterized time evolution, while chaos in the top, which sets in above a sharp threshold value of the Trotter step size, corresponds to the proliferation of Trotter errors. We show the possibility to analyze this phenomenology in a wide variety of experimental realizations of the kicked top, ranging from single atomic spins to trapped-ion quantum simulators which implement DQS of all-to-all interacting spin-1/2 systems. These platforms thus enable in-depth studies of Trotter errors and their relation to signatures of quantum chaos, including the growth of out-of-time-ordered correlators.
Abstract
Background
Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU ...survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients.
Methods
673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival.
Results
Most patients were between 50 and 70 years of age. PaO
2
/FiO
2
ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (
p
= 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (
p
= 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events.
Conclusions
Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival.
Trial registration
Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020,
https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964
.
Graphical abstract
The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual ...in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 -0.5;-0.3 and -0.2 -0.3;-0.2 points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 -19.6;-11.17 ng/mL; -17,52 -70;44 mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 -23.6;-12.8 ng/mL; -2.6 -3.0;-2.2 pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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