101 results on '"Ochsenbein AF"'
Search Results
2. Les anticorps monoclonaux dans le traitement du cancer
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Farese, SA, primary and Ochsenbein, AF, additional
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- 2008
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3. Monoklonale Antikörpertherapie in der Onkologie
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Farese, SA, primary and Ochsenbein, AF, additional
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- 2008
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4. Anticorps monoclonaux «magic bullets»?
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Ochsenbein, AF, primary
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- 2008
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5. Monoklonale Antikörper - «magic bullets»?
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Ochsenbein, AF, primary
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- 2008
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6. Anticorps monoclonaux comme substances thérapeutiques
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Ochsenbein, AF, primary
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- 2008
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7. Monoklonale Antikörper als therapeutische Substanzen
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Ochsenbein, AF, primary
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- 2008
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8. Oncologie: Thérapie ciblée contre le carcinome rénal?
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Ochsenbein, AF, primary
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- 2007
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9. Onkologie: Zielgerichtet gegen das Nierenzellkarzinom?
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Ochsenbein, AF, primary
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- 2007
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10. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.
- Author
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Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M, and Stupp, Roger
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- 2010
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11. Quantification of fetomaternal hemorrhage by fluorescence microscopy is equivalent to flow cytometry.
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Ochsenbein-Imhof N, Ochsenbein AF, Seifert B, Huch A, Hucyh R, Zimmermann R, Ochsenbein-Imhof, Nadin, Ochsenbein, A F, Seifert, B, Huch, Albert, Huch, Renate, and Zimmermann, Roland
- Abstract
Background: The quantification of fetal cells in the maternal circulation remains an important goal to determine the amount of anti-D necessary to prevent active immunization of a D- mother giving birth to a D+ baby. Underestimation of fetomaternal hemorrhage (FMH) results in inefficient anti-D prophylaxis and maternal immunization; overestimation of FMH results in higher doses of passively transferred anti-D, higher costs, and the risk of disease transmission. Thus, a reliable method to quantitatively assess FMH is necessary.Study Design and Methods: Serial dilutions of artificial FMH were quantitatively measured by three different methods: flow cytometry, fluorescence microscopy (each after anti-D staining), and by the Kleihauer-Betke test. The accuracy and precision of the three methods were compared by statistical analysis.Results: Fluorescence microscopy and flow cytometry were comparably accurate and precise in quantifying FMH. In contrast, the accuracy of the Kleihauer-Betke test was poor, resulting in substantial overestimation of FMH in the samples with lower fetal cell concentrations.Conclusion: Anti-D flow cytometry and fluorescence microscopy for detection of fetal cells offer equally reliable and precise methods in contrast to the Kleihauer-Betke test. Fluorescence microscopy may be established as standard to quantify FMH in clinical practice because it is comparable to flow cytometry; in addition, it is time saving and is less expensive. [ABSTRACT FROM AUTHOR]- Published
- 2002
12. Siglec-7 represents a lycol-immune checkpoint on non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities
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Haas, Q, primary, Markov, N, additional, Muerner, L, additional, Rubino, V, additional, Benjak, A, additional, Haubitz, M, additional, Baerlocher, GM, additional, Ng, KYC, additional, Münz, C, additional, Riether, C, additional, Ochsenbein, AF, additional, Simon, H, additional, and von Guten, S, additional
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13. IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
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Rubino V, Hüppi M, Höpner S, Tortola L, Schnüriger N, Legenne H, Taylor L, Voggensperger S, Keller I, Bruggman R, Kronig MN, Bacher U, Kopf M, Ochsenbein AF, and Riether C
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- Animals, Humans, Mice, Immunotherapy, Adoptive methods, Female, Mice, Inbred C57BL, Male, Receptors, Interleukin-21 metabolism, Receptors, Interleukin-21 genetics, Cell Differentiation drug effects, Xenograft Model Antitumor Assays, Cell Line, Tumor, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes drug effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute metabolism, Cytarabine pharmacology, Cytarabine therapeutic use, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Interleukins metabolism, Signal Transduction drug effects
- Abstract
Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4
+ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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14. IL-9 secreted by leukemia stem cells induces Th1-skewed CD4+ T cells, which promote their expansion.
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Radpour R, Simillion C, Wang B, Abbas HA, Riether C, and Ochsenbein AF
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- Humans, Cell Proliferation, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism, Tumor Microenvironment immunology, Receptors, Interleukin-9 genetics, Receptors, Interleukin-9 metabolism, Interferon-gamma metabolism, Histone-Lysine N-Methyltransferase genetics, Interleukin-9 genetics, Interleukin-9 metabolism, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells immunology, Th1 Cells immunology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism
- Abstract
Abstract: In acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)-producing (Th9) CD4+ T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-γ) and tumor necrosis factor α (TNF-α). IFN-γ and, to a lesser extent, TNF-α produced by activated CD4+ T cells induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF, and IFNG expression in BM-infiltrating CD4+ T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-γ and TNF-α., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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15. The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.
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Bianchi M, Reichen C, Croset A, Fischer S, Eggenschwiler A, Grübler Y, Marpakwar R, Looser T, Spitzli P, Herzog C, Villemagne D, Schiegg D, Abduli L, Iss C, Neculcea A, Franchini M, Lekishvili T, Ragusa S, Zitt C, Kaufmann Y, Auge A, Hänggi M, Ali W, Frasconi TM, Wullschleger S, Schlegel I, Matzner M, Lüthi U, Schlereth B, Dawson KM, Kirkin V, Ochsenbein AF, Grimm S, Reschke N, Riether C, Steiner D, Leupin N, and Goubier A
- Subjects
- Humans, Animals, Mice, Interleukin-3 Receptor alpha Subunit immunology, Interleukin-3 Receptor alpha Subunit metabolism, Xenograft Model Antitumor Assays, Sialic Acid Binding Ig-like Lectin 3 metabolism, Sialic Acid Binding Ig-like Lectin 3 immunology, CD3 Complex immunology, Cell Line, Tumor, Cytotoxicity, Immunologic, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute pathology, Neoplastic Stem Cells immunology, Neoplastic Stem Cells metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057)., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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16. Author Correction: Tumour mutations in long noncoding RNAs enhance cell fitness.
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Esposito R, Lanzós A, Uroda T, Ramnarayanan S, Büchi I, Polidori T, Guillen-Ramirez H, Mihaljevic A, Merlin BM, Mela L, Zoni E, Hovhannisyan L, McCluggage F, Medo M, Basile G, Meise DF, Zwyssig S, Wenger C, Schwarz K, Vancura A, Bosch-Guiteras N, Andrades Á, Tham AM, Roemmele M, Medina PP, Ochsenbein AF, Riether C, Kruithof-de Julio M, Zimmer Y, Medová M, Stroka D, Fox A, and Johnson R
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- 2023
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17. Molecular and immunological mechanisms of clonal evolution in multiple myeloma.
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Forster S, Radpour R, and Ochsenbein AF
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- Humans, Plasma Cells metabolism, Bone Marrow metabolism, Clonal Evolution genetics, Tumor Microenvironment genetics, Multiple Myeloma therapy, Multiple Myeloma drug therapy, Hematologic Neoplasms
- Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Forster, Radpour and Ochsenbein.)
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- 2023
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18. IL-33-ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways.
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Naef P, Radpour R, Jaeger-Ruckstuhl CA, Bodmer N, Baerlocher GM, Doehner H, Doehner K, Riether C, and Ochsenbein AF
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- Animals, Mice, Interleukin-1 Receptor-Like 1 Protein, NF-kappa B, Wnt Signaling Pathway, Interleukin-33 genetics, Leukemia, Myeloid
- Abstract
Cell stemness is characterized by quiescence, pluripotency, and long-term self-renewal capacity. Therapy-resistant leukemic stem cells (LSCs) are the primary cause of relapse in patients with chronic and acute myeloid leukemia (CML and AML). However, the same signaling pathways frequently support stemness in both LSCs and normal hematopoietic stem cells (HSCs), making LSCs difficult to therapeutically target. In cell lines and patient samples, we found that interleukin-33 (IL-33) signaling promoted stemness only in leukemia cells in a subtype-specific manner. The IL-33 receptor ST2 was abundant on the surfaces of CD34
+ BCR/ABL1 CML and CD34+ AML cells harboring AML1/ETO and DEK/NUP214 translocations or deletion of chromosome 9q [del(9q)]. The cell surface abundance of ST2, which was lower or absent on other leukemia subtypes and HSCs, correlated with stemness, activated Wnt signaling, and repressed Notch signaling. IL-33-ST2 signaling promoted the maintenance and expansion of AML1/ETO-, DEK/NUP214-, and BCR/ABL1-positive LSCs in culture and in mice by activating Wnt, MAPK, and NF-κB signaling. Wnt signaling and its inhibition of the Notch pathway up-regulated the expression of the gene encoding ST2, thus forming a cell-autonomous loop. IL-33-ST2 signaling promoted the resistance of CML cells to the tyrosine kinase inhibitor (TKI) nilotinib and of AML cells to standard chemotherapy. Thus, inhibiting IL-33-ST2 signaling may target LSCs to overcome resistance to chemotherapy or TKIs in these subtypes of leukemia.- Published
- 2023
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19. Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.
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Pabst T, Vey N, Adès L, Bacher U, Bargetzi M, Fung S, Gaidano G, Gandini D, Hultberg A, Johnson A, Ma X, Müller R, Nottage K, Papayannidis C, Recher C, Riether C, Shah P, Tryon J, Xiu L, and Ochsenbein AF
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- Humans, Azacitidine adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Cusatuzumab is a high-affinity, anti-CD70 monoclonal antibody under investigation in acute myeloid leukemia (AML). This two-part, open-label, multicenter, phase I/II trial evaluated cusatuzumab plus azacitidine in patients with newly diagnosed AML ineligible for intensive chemotherapy. Patients received a single dose of cusatuzumab at one of four dose levels (1, 3, 10, or 20 mg/kg) 14 days before starting combination therapy. In phase I dose escalation, cusatuzumab was then administered on days 3 and 17, in combination with azacitidine (75 mg/m2) on days 1-7, every 28 days. The primary objective in phase I was to determine the recommended phase II dose (RP2D) of cusatuzumab plus azacitidine. The primary objective in phase II was efficacy at the RP2D (selected as 10 mg/kg). Thirty-eight patients were enrolled: 12 in phase I (three per dose level; four with European LeukemiaNet 2017 adverse risk) and 26 in phase II (21 with adverse risk). An objective response (≥partial remission) was achieved by 19/38 patients (including 8/26 in phase II); 14/38 achieved complete remission. Eleven patients (37.9%) achieved an objective response among the 29 patients in phase I and phase II treated at the RP2D. At a median follow-up of 10.9 months, median duration of first response was 4.5 months and median overall survival was 11.5 months. The most common treatment-emergent adverse events were infections (84.2%) and hematologic toxicities (78.9%). Seven patients (18.4%) reported infusion-related reactions, including two with grade 3 events. Thus, cusatuzumab/azacitidine appears generally well tolerated and shows preliminary efficacy in this setting. Investigation of cusatuzumab combined with current standard-of-care therapy, comprising venetoclax and azacitidine, is ongoing.
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- 2023
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20. Tumour mutations in long noncoding RNAs enhance cell fitness.
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Esposito R, Lanzós A, Uroda T, Ramnarayanan S, Büchi I, Polidori T, Guillen-Ramirez H, Mihaljevic A, Merlin BM, Mela L, Zoni E, Hovhannisyan L, McCluggage F, Medo M, Basile G, Meise DF, Zwyssig S, Wenger C, Schwarz K, Vancura A, Bosch-Guiteras N, Andrades Á, Tham AM, Roemmele M, Medina PP, Ochsenbein AF, Riether C, Kruithof-de Julio M, Zimmer Y, Medová M, Stroka D, Fox A, and Johnson R
- Subjects
- Animals, Mice, Mutation, Oncogenes, Genomics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Neoplasms genetics
- Abstract
Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic "driver" mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness., (© 2023. The Author(s).)
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- 2023
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21. MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.
- Author
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Yang H, Gao Y, Xu D, Xu K, Liang SQ, Yang Z, Scherz A, Hall SRR, Forster S, Berezowska S, Yao F, Ochsenbein AF, Marti TM, Kocher GJ, Schmid RA, Dorn P, and Peng RW
- Abstract
Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis., (© 2023. The Author(s).)
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- 2023
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22. Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance.
- Author
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Bührer ED, Amrein MA, Forster S, Isringhausen S, Schürch CM, Bhate SS, Brodie T, Zindel J, Stroka D, Sayed MA, Nombela-Arrieta C, Radpour R, Riether C, and Ochsenbein AF
- Subjects
- Humans, Mice, Animals, Spleen, Neoplastic Stem Cells metabolism, Macrophages metabolism, Disease Progression, Tumor Microenvironment, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid genetics
- Abstract
Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy., (© 2022. The Author(s).)
- Published
- 2022
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23. Siglec-7 represents a glyco-immune checkpoint for non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities.
- Author
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Haas Q, Markov N, Muerner L, Rubino V, Benjak A, Haubitz M, Baerlocher GM, Ng CKY, Münz C, Riether C, Ochsenbein AF, Simon HU, and von Gunten S
- Subjects
- Antigens, Differentiation, Myelomonocytic, CD8-Positive T-Lymphocytes, Humans, Lectins, Sialic Acid Binding Immunoglobulin-like Lectins, Actins, Leukemia, Myeloid, Acute
- Abstract
While inhibitory Siglec receptors are known to regulate myeloid cells, less is known about their expression and function in lymphocytes subsets. Here we identified Siglec-7 as a glyco-immune checkpoint expressed on non-exhausted effector memory CD8+ T cells that exhibit high functional and metabolic capacities. Seahorse analysis revealed higher basal respiration and glycolysis levels of Siglec-7
+ CD8+ T cells in steady state, and particularly upon activation. Siglec-7 polarization into the T cell immune synapse was dependent on sialoglycan interactions in trans and prevented actin polarization and effective T cell responses. Siglec-7 ligands were found to be expressed on both leukemic stem cells and acute myeloid leukemia (AML) cells suggesting the occurrence of glyco-immune checkpoints for Siglec-7+ CD8+ T cells, which were found in patients' peripheral blood and bone marrow. Our findings project Siglec-7 as a glyco-immune checkpoint and therapeutic target for T cell-driven disorders and cancer., Competing Interests: SG receives remuneration for serving on the scientific advisory board of Palleon Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Haas, Markov, Muerner, Rubino, Benjak, Haubitz, Baerlocher, Ng, Münz, Riether, Ochsenbein, Simon and von Gunten.)- Published
- 2022
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24. Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities.
- Author
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Esposito R, Polidori T, Meise DF, Pulido-Quetglas C, Chouvardas P, Forster S, Schaerer P, Kobel A, Schlatter J, Kerkhof E, Roemmele M, Rice ES, Zhu L, Lanzós A, Guillen-Ramirez HA, Basile G, Carrozzo I, Vancura A, Ullrich S, Andrades A, Harvey D, Medina PP, Ma PC, Haefliger S, Wang X, Martinez I, Ochsenbein AF, Riether C, and Johnson R
- Abstract
Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemoresistance, and migration across two cell backgrounds. Integrative analysis of these data outperforms conventional "dropout" screens in identifying cancer genes while prioritizing disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether, 80 high-confidence oncogenic lncRNAs are active in NSCLC, which tend to be amplified and overexpressed in tumors. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 ( CHiLL1 ) and GCAWKR , whose knockdown consistently suppressed cancer hallmarks in two- and three-dimension tumor models. Molecular phenotyping reveals that CHiLL1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks. This work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities., Competing Interests: T.P., R.E., and R.J. have filed a patent application (21202363.4) relating to the therapeutic targeting of lncRNAs identified here. Applicant: University of Bern. R.J. is a paid consultant for NextRNA (USA)., (© 2022 The Author(s).)
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- 2022
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25. Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells.
- Author
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Hinterbrandner M, Rubino V, Stoll C, Forster S, Schnüriger N, Radpour R, Baerlocher GM, Ochsenbein AF, and Riether C
- Subjects
- Animals, Chronic Disease, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Mice, Immunotherapy methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Receptors, OX40 metabolism, T-Lymphocytes, Regulatory immunology, Tumor Escape immunology
- Abstract
Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by CD8+ cytotoxic T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML BM, protected LSCs from MHC class I-dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4 signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulators of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost antileukemic immunity in CML.
- Published
- 2021
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26. SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial.
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Rothschild SI, Zippelius A, Eboulet EI, Savic Prince S, Betticher D, Bettini A, Früh M, Joerger M, Lardinois D, Gelpke H, Mauti LA, Britschgi C, Weder W, Peters S, Mark M, Cathomas R, Ochsenbein AF, Janthur WD, Waibel C, Mach N, Froesch P, Buess M, Bohanes P, Godar G, Rusterholz C, Gonzalez M, and Pless M
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Chemotherapy, Adjuvant, Cisplatin therapeutic use, Docetaxel therapeutic use, Female, Humans, Immune Checkpoint Inhibitors adverse effects, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Pneumonectomy, Progression-Free Survival, Switzerland, Time Factors, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Neoadjuvant Therapy adverse effects, Neoadjuvant Therapy mortality
- Abstract
Purpose: For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab., Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m
2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%., Results: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related., Conclusion: The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%., Competing Interests: Sacha I. RothschildConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eisai, Roche, Novartis, Merck Serono, MSD Oncology, Pfizer, Takeda, AbbVieResearch Funding: Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, AbbVieExpert Testimony: Roche, AstraZeneca, Bristol Myers SquibbTravel, Accommodations, Expenses: Roche Pharma AG, Lilly, Bristol Myers Squibb, AstraZeneca, Merck Sharp & Dohme, Amgen Alfred ZippeliusHonoraria: BMSi, MSD, Roche, NBE Therapeutics, ACM Pharma, Hookipa Biotech, BeyondSpring PharmaceuticalsResearch Funding: Roche, NBE Therapeutics, Secarna, ACM Pharma, Hookipa Biotech, Beyondsprings Spasenija Savic PrinceHonoraria: NovartisConsulting or Advisory Role: Diaceutics Ireland Limited, Merck (Schweiz) AG, AstraZeneca AG Daniel BetticherTravel, Accommodations, Expenses: Bayer Adrienne BettiniHonoraria: MSD OncologyConsulting or Advisory Role: MSD Oncology, AstraZenecaTravel, Accommodations, Expenses: Janssen Oncology Martin FrühConsulting or Advisory Role: BMS, AstraZeneca, MSD, Takeda, Roche, LillySpeakers' Bureau: PfizerResearch Funding: BMS, AstraZeneca Markus JoergerConsulting or Advisory Role: Novartis, AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Debiopharm Group, Merck, Roche, SanofiResearch Funding: AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Immunophotonics, InnoMedica, Janssen Oncology, Lilly, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Takeda Laetitia A. MautiConsulting or Advisory Role: Takeda, Roche, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, PfizerTravel, Accommodations, Expenses: Takeda, Bristol Myers Squibb, Merck, Roche, AstraZeneca Christian BritschgiConsulting or Advisory Role: AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag, Boehringer IngelheimTravel, Accommodations, Expenses: AstraZeneca, Takeda Walter WederConsulting or Advisory Role: AstraZeneca, Covidien/MedtronicSpeakers' Bureau: AstraZeneca, Covidien/MedtronicTravel, Accommodations, Expenses: AstraZeneca, Covidien/Medtronic Solange PetersHonoraria: Roche, Bristol Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Takeda, Illumina, MedscapeConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen, Regeneron, Merck Serono, Boehringer Ingelheim, Takeda, Lilly, AbbVie, Bayer, Biocartis, Debiopharm Group, Illumina, PharmaMar, Sanofi, Seattle Genetics, Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent, Clovis Oncology, Vaccibody, Phosplatin TherapeuticsResearch Funding: Roche, BMS, MSD, Amgen, Lilly, AstraZeneca, Pfizer, Illumina, Merck Serono, Novartis, Biodesix, Boehringer Ingelheim, Iovance Biotherapeutics, Phosplatin TherapeuticsTravel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology Michael MarkConsulting or Advisory Role: Roche, AstraZeneca, Takeda, BMS, MSD OncologyTravel, Accommodations, Expenses: Pfizer, Roche, Takeda Richard CathomasHonoraria: Janssen-Cilag, Astellas Pharma, BMS, Debiopharm GroupConsulting or Advisory Role: Astellas Pharma, Bristol Myers Squibb, Pfizer, Roche, MSD Oncology, Janssen-Cilag, Bayer, Sanofi, IpsenTravel, Accommodations, Expenses: AstraZeneca Adrian F. OchsenbeinConsulting or Advisory Role: TolremoResearch Funding: argenxPatents, Royalties, Other Intellectual Property: Patent on the anti-CD70 antibody cusatuzumab Wolf-Dieter JanthurConsulting or Advisory Role: Roche, Takeda, MSD, Novartis Nicolas MachStock and Other Ownership Interests: MaxVAX SAResearch Funding: MaxiVaxPatents, Royalties, Other Intellectual Property: I am an inventor on patent owned by MaxiVAX SA and on patent co-owned by Geneva University Hospital and MaxiVAX SAUncompensated Relationships: MaxiVax Patrizia FroeschConsulting or Advisory Role: Pfizer, Takeda, Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Bayer Pierre BohanesHonoraria: MSD, BayerTravel, Accommodations, Expenses: Janssen Corinne RusterholzEmployment: Roche Miklos PlessHonoraria: Janssen-CilagConsulting or Advisory Role: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai Europe, MSD Oncology, Novartis, Pfizer/EMD Serono, Roche, Takeda, Merck SeronoExpert Testimony: TakedaTravel, Accommodations, Expenses: Vifor Pharma, Bristol Myers Squibb, Boehringer Ingelheim, AstraZenecaNo other potential conflicts of interest were reported.- Published
- 2021
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27. Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.
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Radpour R, Stucki M, Riether C, and Ochsenbein AF
- Abstract
Background: Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML., Methods: To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4
+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1 ., Results: We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1 , as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells., Conclusions: Our results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Radpour, Stucki, Riether and Ochsenbein.)- Published
- 2021
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28. LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.
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Höpner SS, Raykova A, Radpour R, Amrein MA, Koller D, Baerlocher GM, Riether C, and Ochsenbein AF
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- Animals, Antigens, CD34 metabolism, Cell Cycle drug effects, Cell Cycle genetics, Cell Proliferation drug effects, DNA Damage, Fluorouracil pharmacology, Gene Expression Regulation, Leukemic drug effects, Hematopoietic Stem Cells drug effects, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Mice, Inbred C57BL, Mice, Knockout, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction drug effects, Mice, Cell Differentiation drug effects, Cell Self Renewal drug effects, Cell Self Renewal genetics, Hematopoietic Stem Cells metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Lymphotoxin beta Receptor metabolism, Neoplastic Stem Cells pathology, Tumor Necrosis Factor Ligand Superfamily Member 14 metabolism
- Abstract
The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
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- 2021
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29. Chemotherapy negatively impacts the tumor immune microenvironment in NSCLC: an analysis of pre- and post-treatment biopsies in the multi-center SAKK19/09 study.
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Amrein MA, Bührer ED, Amrein ML, Li Q, Rothschild S, Riether C, Jaggi R, Savic-Prince S, Bubendorf L, Gautschi O, and Ochsenbein AF
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- Biopsy, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms pathology, Male, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung surgery, Gene Expression genetics, Lung Neoplasms genetics, Lung Neoplasms surgery, Tumor Microenvironment genetics
- Abstract
Background: Over the past few years, immune checkpoint inhibitors have changed the therapeutic landscape of non-small-cell lung cancer (NSCLC). Response to immune checkpoint inhibitors correlates with a pre-existing anti-tumoral immune response. Checkpoint inhibitors have been introduced as second-line therapy and are only very recently used as monotherapy or in combination with chemotherapy as first-line treatment of NSCLC. However, the effect of conventional first-line platinum-based chemotherapy on the immune infiltrate in the tumor is largely unknown., Methods: We measured the gene expression of a custom set of 201 cancer- and immune-related genes in 100 NSCLC tumor biopsies collected before chemotherapy and 33 re-biopsies after platinum-based chemotherapy at the time point of progression. For 29 patients matched pre- and post-chemotherapy samples could be evaluated., Results: We identified a cluster of 47 co-expressed immune genes, including PDCD1 (PD1) and CD274 (PD-L1), along with three other co-expression clusters. Chemotherapy decreased the average gene expression of the immune cluster while no effect was observed on the other three cluster. Within this immune cluster, CTLA4, LAG3, TNFRSF18, CD80 and FOXP3 were found to be significantly decreased in patient-matched samples after chemotherapy., Conclusion: Our results suggest that conventional platinum-based chemotherapy negatively impacts the immune microenvironment at the time point of secondary progression.
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- 2021
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30. Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells.
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Riether C, Radpour R, Kallen NM, Bürgin DT, Bachmann C, Schürch CM, Lüthi U, Arambasic M, Hoppe S, Albers CE, Baerlocher GM, and Ochsenbein AF
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- Animals, Dopamine D2 Receptor Antagonists pharmacology, Humans, Metoclopramide pharmacology, Mice, Dopamine D2 Receptor Antagonists therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Metoclopramide therapeutic use
- Abstract
Self-renewal is a key characteristic of leukemia stem cells (LSCs) responsible for the development and maintenance of leukemia. In this study, we identify CD93 as an important regulator of self-renewal and proliferation of murine and human LSCs, but not hematopoietic stem cells (HSCs). The intracellular domain of CD93 promotes gene transcription via the transcriptional regulator SCY1-like pseudokinase 1 independently of ligation of the extracellular domain. In a drug library screen, we identify the anti-emetic agent metoclopramide as an efficient blocker of CD93 signaling. Metoclopramide treatment reduces murine and human LSCs in vitro and prolongs survival of chronic myeloid leukemia (CML) mice through downregulation of pathways related to stemness and proliferation in LSCs. Overall, these results identify CD93 signaling as an LSC-specific regulator of self-renewal and proliferation and a targetable pathway to eliminate LSCs in CML., Competing Interests: Declaration of interests The authors declare no competing interests. C.R. and A.F.O. are inventors on patent EP 19207529.9 submitted by University of Bern that covers CD93 inhibitors for the treatment of cancer., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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31. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents.
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Riether C, Pabst T, Höpner S, Bacher U, Hinterbrandner M, Banz Y, Müller R, Manz MG, Gharib WH, Francisco D, Bruggmann R, van Rompaey L, Moshir M, Delahaye T, Gandini D, Erzeel E, Hultberg A, Fung S, de Haard H, Leupin N, and Ochsenbein AF
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- Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Azacitidine therapeutic use, DNA Methylation drug effects, DNA Methylation genetics, Humans, Leukemia, Myeloid, Acute pathology, Treatment Outcome, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, Antineoplastic Agents therapeutic use, CD27 Ligand antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Neoplastic Stem Cells drug effects
- Abstract
Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse
1,2 . Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5 . Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10- 3 . Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.- Published
- 2020
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32. Genetic Alterations Impact Immune Microenvironment Interactions in Follicular Lymphoma.
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Riether C and Ochsenbein AF
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- Cathepsins, Germinal Center, Humans, Tumor Microenvironment genetics, Lymphoma, Follicular genetics
- Abstract
Interactions between germinal center B cells and immune cells in the microenvironment can play integral roles in transformation and growth of follicular lymphoma (FL). Three recent studies, two in this issue of Cancer Cell and one in Cell Reports, elucidate how genetic alterations in CTSS and EZH2 impact these interactions, with implications for FL immunotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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33. TNIK signaling imprints CD8 + T cell memory formation early after priming.
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Jaeger-Ruckstuhl CA, Hinterbrandner M, Höpner S, Correnti CE, Lüthi U, Friedli O, Freigang S, Al Sayed MF, Bührer ED, Amrein MA, Schürch CM, Radpour R, Riether C, and Ochsenbein AF
- Subjects
- Animals, Apoptosis, CD8-Positive T-Lymphocytes cytology, Cell Differentiation, Humans, Immunologic Memory, Lymphocyte Activation, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis physiopathology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus physiology, Mice, Mice, Knockout, Protein Serine-Threonine Kinases genetics, Signal Transduction, Wnt Signaling Pathway, CD8-Positive T-Lymphocytes immunology, Lymphocytic Choriomeningitis immunology, Protein Serine-Threonine Kinases immunology
- Abstract
Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8
+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of β-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.- Published
- 2020
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34. CD8 + T cells expand stem and progenitor cells in favorable but not adverse risk acute myeloid leukemia.
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Radpour R, Riether C, Simillion C, Höpner S, Bruggmann R, and Ochsenbein AF
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- Adult, Aged, Aged, 80 and over, Cell Proliferation physiology, Cytokines immunology, Humans, Interleukin-3 immunology, Male, Middle Aged, Prognosis, Prospective Studies, Young Adult, Bone Marrow immunology, CD8-Positive T-Lymphocytes immunology, Leukemia, Myeloid, Acute immunology, Stem Cells immunology
- Abstract
CD8
+ T cell immunosurveillance is crucial in solid tumors and T cell dysfunction leads to tumor progression. In contrast, the role of CD8+ T cells in the control of leukemia is less clear. We characterized the molecular signature of leukemia stem/progenitor cells (LSPCs) and paired CD8+ T cells in patients with acute myeloid leukemia (AML). Epigenetic alterations via histone deacetylation reduced the expression of immune-related genes in bone marrow (BM)-infiltrating CD8+ T cells. Surprisingly, a silenced gene expression pattern in CD8+ T cells significantly correlated with an improved prognosis. To define interactions between CD8+ T cells and LSPCs, we performed comprehensive correlative network modeling. This analysis indicated that CD8+ T cells contribute to the maintenance/expansion of LSPCs, particularly in favorable risk AML. Functionally, CD8+ T cells in favorable AML induced the expansion of LSPCs by stimulating the autocrine production of important hematopoietic cytokines such as interleukin (IL)-3. In contrast, LSPCs in aggressive AML were characterized by a higher activation of stemness/proliferation-related pathways and develop independent of BM CD8+ T cells. Overall, our study indicates that CD8+ T cells support and expand LSPCs in favorable risk AML whereas intermediate and adverse risk AML possess the intrinsic molecular abnormalities to develop independently.- Published
- 2019
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35. T-cell-Secreted TNFα Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer.
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Al Sayed MF, Amrein MA, Bührer ED, Huguenin AL, Radpour R, Riether C, and Ochsenbein AF
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- Animals, Bone Marrow Cells immunology, Bone Marrow Cells pathology, CD4-Positive T-Lymphocytes pathology, Cell Differentiation immunology, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells pathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myeloid Progenitor Cells immunology, Myeloid Progenitor Cells pathology, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells pathology, CD4-Positive T-Lymphocytes immunology, Myelopoiesis immunology, Neoplasms, Experimental immunology, Neoplasms, Experimental pathology, Tumor Necrosis Factor-alpha immunology
- Abstract
Hematopoiesis in patients with cancer is characterized by reduced production of red blood cells and an increase in myelopoiesis, which contributes to the immunosuppressive environment in cancer. Some tumors produce growth factors that directly stimulate myelopoiesis such as G-CSF or GM-CSF. However, for a majority of tumors that do not directly secrete hematopoietic growth factors, the mechanisms involved in the activation of myelopoiesis are poorly characterized. In this study, we document in different murine tumor models activated hematopoiesis with increased proliferation of long-term and short-term hematopoietic stem cells and myeloid progenitor cells. As a consequence, the frequency of myeloid-derived suppressor cells and its ratio to CD8
+ T cells increased in tumor-bearing mice. Activation of hematopoiesis and myeloid differentiation in tumor-bearing mice was induced by TNFα, which was mainly secreted by activated CD4+ T cells. Therefore, the activated adaptive immune system in cancer induces emergency myelopoiesis and immunosuppression. SIGNIFICANCE: These findings characterize a regulatory circuit linking activated T cells to suppression of tumor-specific immune responses, providing a conceptual advance in the understanding of emergency-hematopoiesis in cancer and opening new targets for therapeutic approaches. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/2/346/F1.large.jpg., (©2018 American Association for Cancer Research.)- Published
- 2019
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36. mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer.
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Liang SQ, Bührer ED, Berezowska S, Marti TM, Xu D, Froment L, Yang H, Hall SRR, Vassella E, Yang Z, Kocher GJ, Amrein MA, Riether C, Ochsenbein AF, Schmid RA, and Peng RW
- Subjects
- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology, Animals, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Mice, Knockout, Proto-Oncogene Proteins p21(ras) genetics, TOR Serine-Threonine Kinases genetics, Adenocarcinoma of Lung enzymology, Drug Resistance, Neoplasm, Lung Neoplasms enzymology, Proto-Oncogene Proteins p21(ras) metabolism, TOR Serine-Threonine Kinases metabolism
- Abstract
Oncogenic KRAS mutations comprise the largest subset of lung cancer defined by genetic alterations, but in the clinic no targeted therapies are available that effectively control mutational KRAS activation. Consequently, patients with KRAS-driven tumors are routinely treated with cytotoxic chemotherapy, which is often transiently effective owing to development of drug resistance. In this study, we show that hyperactivated mammalian target of rapamycin (mTOR) pathway is a characteristic hallmark of KRAS-mutant lung adenocarcinoma after chemotherapy treatment, and that KRAS-mutant lung cancer cells rely on persistent mTOR signaling to resist chemotherapeutic drugs. Coherently, mTOR inhibition circumvents the refractory phenotype and restores sensitivity of resistant KRAS-mutant lung cancer cells to chemotherapy. Importantly, drug combinations of clinically approved mTOR inhibitors and chemotherapy drugs synergize in inhibiting cell proliferation of KRAS-mutant cancer cells in vitro and in vivo, and the efficacy of this combination treatment correlates with the magnitude of mTOR activity induced by chemotherapy alone. These results pinpoint mTOR as a mechanism of resistance to chemotherapy in KRAS-mutant lung cancer and validate a rational and readily translatable strategy that combines mTOR inhibitors with standard chemotherapy to treat KRAS-mutant adenocarcinoma, the most common and deadliest lung cancer subset.
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- 2019
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37. Multimodal Treatment in Operable Stage III NSCLC: A Pooled Analysis on Long-Term Results of Three SAKK trials (SAKK 16/96, 16/00, and 16/01).
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Früh M, Betticher DC, Stupp R, Xyrafas A, Peters S, Ris HB, Mirimanoff RO, Ochsenbein AF, Schmid R, Matzinger O, Stahel RA, Weder W, Guckenberger M, Rothschild SI, Lardinois D, Mach N, Mark M, Gautschi O, Thierstein S, Biaggi Rudolf C, and Pless M
- Subjects
- Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms pathology, Neoplasm Staging, Carcinoma, Non-Small-Cell Lung surgery, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms surgery, Lung Neoplasms therapy
- Abstract
Introduction: Long-term data on outcomes of operable stage III NSCLC are scarce., Methods: Individual patient data from 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the eighth (denoted with an asterisk [*]) versus the sixth TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following 3 cycles of induction chemotherapy (trimodal) or neoadjuvant chemotherapy alone (bimodal)., Results: With the sixth version, the 5- and 10-year survival rates were 38% and 28% for stage IIIA, respectively, and 36% and 24% for stage IIIB, respectively. Factors associated with improved 5-year overall survival were younger age, R0 resection, and pathologic complete remission (pCR) (p = 0.043, p < 0.001 and p = 0.009). With the eighth TNM staging version, 162 patients were moved from stage IIIA to IIIB*. The 5- and 10-year survival rates were 41% and 29% for stage IIIA*, respectively, and 35% and 27% for stage IIIB* patients, respectively. There was no difference in the bi- versus trimodal group with regard to median overall survival (28 months [95% confidence interval (CI): 21-39 months] and 37 months [95% CI: 24-51 months], p = 0.9) and event-free survival (12 months [95% CI: 9-15 months] versus 13 months [95% CI: 10-22 months], p = 0.71)., Conclusions: We showed favorable 10-year survival rates of 29% and 27% in stage IIIA* and IIIB*, respectively. Younger age, R0 resection, and pathologic complete response were associated with improved long-term survival. Outcomes using the sixth versus eighth edition of the TNM classification were similar in operable stage III NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)
- Published
- 2019
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38. T cell inhibitory mechanisms in a model of aggressive Non-Hodgkin's Lymphoma.
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Hilmenyuk T, Ruckstuhl CA, Hayoz M, Berchtold C, Nuoffer JM, Solanki S, Keun HC, Beavis PA, Riether C, and Ochsenbein AF
- Abstract
A reduced immune surveillance due to immune deficiency or treatment with immunosuppressive drugs is associated with a higher risk to develop aggressive Non-Hodgkin's lymphoma (NHL). Nevertheless, NHL also develops in immunocompetent patients indicating an escape from the immune system. T cell function in advanced aggressive lymphoma is not well characterized and the molecular mechanisms how malignant B cells influence T cell function are ill-defined. We therefore studied T cell function in Eμ-myc transgenic mice that develop an aggressive B cell lymphoma with some similarities to human Burkitt-lymphoma (BL). In advanced lymphoma, the number of T cells was severely reduced and the remaining CD4
+ and CD8+ T cells lost the capacity to produce effector cytokines and expand upon re-stimulation. T cells in lymphoma-bearing mice were characterized by the expression of the immune inhibitory molecules programmed death (PD)-1, 2B4 and lymphocyte activation protein (LAG)-3. The proto-oncogene c-Myc not only drives cell proliferation and disease progression but also induces apoptosis of the malignant cells. We found that apoptotic lymphoma cells release purine metabolites that inhibit T cell function. Taken together, our data document that the characteristic high cell turnover and apoptotic rate in aggressive NHL induce a severe T cell dysfunction mediated by several immune-inhibitory mechanisms including ligation of inhibitory ligands and purine metabolites. Blocking a single mechanism only partially restored T cell function and did not increase survival of lymphoma mice.- Published
- 2017
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39. CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies.
- Author
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Al Sayed MF, Ruckstuhl CA, Hilmenyuk T, Claus C, Bourquin JP, Bornhauser BC, Radpour R, Riether C, and Ochsenbein AF
- Subjects
- Animals, B-Lymphocytes pathology, CD27 Ligand genetics, Gene Expression, Humans, Immunologic Surveillance, Interferon-gamma genetics, Interferon-gamma immunology, Killer Cells, Natural pathology, Ligands, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Mice, Mice, Knockout, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Signal Transduction, Survival Analysis, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic pathology, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory pathology, Transplantation, Heterologous, Tumor Necrosis Factor Receptor Superfamily, Member 7 deficiency, Tumor Necrosis Factor Receptor Superfamily, Member 7 genetics, B-Lymphocytes immunology, CD27 Ligand immunology, Cytotoxicity, Immunologic, Killer Cells, Natural immunology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 immunology
- Abstract
The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non-Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ-producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc-expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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40. Bevacizumab Plus Pemetrexed Versus Pemetrexed Alone as Maintenance Therapy for Patients With Advanced Nonsquamous Non-Small-cell Lung Cancer: Update From the Swiss Group for Clinical Cancer Research (SAKK) 19/09 Trial.
- Author
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Gautschi O, Rothschild SI, Li Q, Matter-Walstra K, Zippelius A, Betticher DC, Früh M, Stahel RA, Cathomas R, Rauch D, Pless M, Peters S, Froesch P, Zander T, Schneider M, Biaggi C, Mach N, and Ochsenbein AF
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols economics, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Cohort Studies, Cost-Benefit Analysis, Female, Follow-Up Studies, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Survival Analysis, Switzerland, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bevacizumab therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Pemetrexed therapeutic use
- Abstract
Background: Pemetrexed and bevacizumab as single agents have been approved for maintenance therapy after platinum-based induction in patients with advanced nonsquamous non-small-cell lung cancer. It is currently unknown whether bevacizumab plus pemetrexed is superior to pemetrexed alone., Patients and Methods: We conducted a nonrandomized phase II trial with 2 sequential cohorts. In the first cohort, 77 patients were treated with 4 cycles of cisplatin, bevacizumab, and pemetrexed every 3 weeks, followed by bevacizumab plus pemetrexed maintenance until progression. In the second cohort, we treated 52 patients without bevacizumab, using maintenance with pemetrexed alone. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), adverse events, and the treatment costs of the 2 cohorts were compared., Results: The median PFS from the time of registration was 6.9 months in cohort 1 and 5.6 months in cohort 2. The ORR was 62.3% in cohort 1% and 44.2% in cohort 2. The PFS (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0; P = .041) and ORR (odds ratio, 2.1; 95% CI, 1.0-4.3; P = .049) were better in cohort 1 than in cohort 2. No OS difference was found (hazard ratio, 1.0; 95% CI, 0.7-1.6; P = .890) after a median follow-up period of 47 months for cohort 1 and 27 months for cohort 2. The rate of grade ≥ 3 adverse events was greater in cohort 1. The treatment costs per patient were on average 1.4 times greater for cohort 1., Conclusion: The addition of bevacizumab increased the ORR and PFS, but not OS, in our nonrandomized trial. Furthermore, the addition of bevacizumab was associated with greater toxicity and higher costs., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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- View/download PDF
41. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.
- Author
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Riether C, Schürch CM, Bührer ED, Hinterbrandner M, Huguenin AL, Hoepner S, Zlobec I, Pabst T, Radpour R, and Ochsenbein AF
- Subjects
- Aged, Animals, Antibodies, Monoclonal therapeutic use, CD27 Ligand antagonists & inhibitors, Germinal Center Kinases, Humans, Leukemia, Myeloid, Acute drug therapy, Mice, Middle Aged, Protein Serine-Threonine Kinases physiology, TNF Receptor-Associated Factor 2 physiology, Tumor Cells, Cultured, Tumor Necrosis Factor Receptor Superfamily, Member 7 antagonists & inhibitors, Tumor Necrosis Factor Receptor Superfamily, Member 7 blood, Tumor Necrosis Factor Receptor Superfamily, Member 7 genetics, Wnt Signaling Pathway physiology, Blast Crisis etiology, CD27 Ligand physiology, Leukemia, Myeloid, Acute pathology, Signal Transduction physiology, Tumor Necrosis Factor Receptor Superfamily, Member 7 physiology
- Abstract
Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML., (© 2017 Riether et al.)
- Published
- 2017
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42. TREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis.
- Author
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Zysset D, Weber B, Rihs S, Brasseit J, Freigang S, Riether C, Banz Y, Cerwenka A, Simillion C, Marques-Vidal P, Ochsenbein AF, Saurer L, and Mueller C
- Subjects
- Animals, Antigens, Ly genetics, Antigens, Ly immunology, Aorta immunology, Aorta pathology, Apolipoproteins E genetics, Apolipoproteins E immunology, Atherosclerosis etiology, Atherosclerosis immunology, Atherosclerosis pathology, Cell Differentiation, Cell Line, Cholesterol administration & dosage, Cytokines genetics, Cytokines immunology, Diet, High-Fat adverse effects, Disease Models, Animal, Dyslipidemias etiology, Dyslipidemias immunology, Dyslipidemias pathology, Female, Foam Cells pathology, Gene Expression Regulation, Humans, Inflammation, Lipid Metabolism immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes immunology, Monocytes pathology, Triggering Receptor Expressed on Myeloid Cells-1 deficiency, Triggering Receptor Expressed on Myeloid Cells-1 immunology, Atherosclerosis genetics, Dyslipidemias genetics, Foam Cells immunology, Lipid Metabolism genetics, Triggering Receptor Expressed on Myeloid Cells-1 genetics
- Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe
-/- mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1-/- Apoe-/- mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation.- Published
- 2016
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- View/download PDF
43. Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09.
- Author
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Gautschi O, Mach N, Rothschild SI, Li Q, Stahel RA, Zippelius A, Cathomas R, Früh M, Betticher DC, Peters S, Rauch D, Feilchenfeldt J, Bubendorf L, Savic S, Jaggi R, Leibundgut EO, Largiadèr C, Brutsche M, Pilop C, Stalder L, Pless M, and Ochsenbein AF
- Subjects
- Adult, Aged, Aged, 80 and over, Bevacizumab administration & dosage, Biopsy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin administration & dosage, Disease-Free Survival, Erlotinib Hydrochloride administration & dosage, Feasibility Studies, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Pemetrexed administration & dosage, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors genetics, Lung Neoplasms drug therapy
- Abstract
Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced non-small-cell lung cancer are promising for further investigation., Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated., Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16 cycles. PFS at 6 months was 70%, median PFS was 14 months, and ORR was 70%. Biopsy at progression was safe and successful in 71% of the cases., Conclusions: Both combination therapies were promising for further studies. Biopsy at progression was feasible and will be part of future SAKK studies to investigate molecular mechanisms of resistance., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
44. Blocking programmed cell death 1 in combination with adoptive cytotoxic T-cell transfer eradicates chronic myelogenous leukemia stem cells.
- Author
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Riether C, Gschwend T, Huguenin AL, Schürch CM, and Ochsenbein AF
- Subjects
- Adoptive Transfer, Animals, Apoptosis, Cell Proliferation, Cells, Cultured, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Mice, Inbred C57BL, Cell- and Tissue-Based Therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Neoplastic Stem Cells pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors, T-Lymphocytes, Cytotoxic transplantation
- Published
- 2015
- Full Text
- View/download PDF
45. Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling.
- Author
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Riether C, Schürch CM, Flury C, Hinterbrandner M, Drück L, Huguenin AL, Baerlocher GM, Radpour R, and Ochsenbein AF
- Subjects
- Animals, Cell Line, Tumor, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Neoplasm Transplantation, Neoplastic Stem Cells drug effects, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, CD27 Ligand metabolism, Drug Resistance, Neoplasm, Neoplastic Stem Cells metabolism, Wnt Signaling Pathway
- Abstract
In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt signaling in LSCs and often results in molecular remission of CML; however, LSCs persist long term despite BCR-ABL1 inhibition, ultimately causing disease relapse. We demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70 in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation. Combining TKIs with CD70 blockade effectively eliminated human CD34(+) CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, targeting TKI-induced expression of CD70 and compensatory Wnt signaling resulting from the CD70/CD27 interaction is a promising approach to overcoming treatment resistance in CML LSCs., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
- Full Text
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46. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms.
- Author
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Mager LF, Riether C, Schürch CM, Banz Y, Wasmer MH, Stuber R, Theocharides AP, Li X, Xia Y, Saito H, Nakae S, Baerlocher GM, Manz MG, McCoy KD, Macpherson AJ, Ochsenbein AF, Beutler B, and Krebs P
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Disease Models, Animal, Humans, Inositol Polyphosphate 5-Phosphatases, Interleukin-1 Receptor-Associated Kinases genetics, Interleukin-1 Receptor-Associated Kinases metabolism, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, Interleukins deficiency, Interleukins genetics, Intracellular Signaling Peptides and Proteins, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mice, Transgenic, Mutant Proteins genetics, Mutant Proteins metabolism, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Myelopoiesis genetics, Myelopoiesis physiology, Myeloproliferative Disorders immunology, Myeloproliferative Disorders metabolism, Nuclear Matrix-Associated Proteins, Phosphoric Monoester Hydrolases deficiency, Phosphoric Monoester Hydrolases genetics, Phosphoric Monoester Hydrolases metabolism, Receptors, Interleukin metabolism, Signal Transduction, Toll-Like Receptors metabolism, Interleukins metabolism, Myeloproliferative Disorders etiology
- Abstract
Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell-derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33-expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.
- Published
- 2015
- Full Text
- View/download PDF
47. CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis.
- Author
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Galli S, Zlobec I, Schürch C, Perren A, Ochsenbein AF, and Banz Y
- Subjects
- Humans, Immunohistochemistry, Leukemia, Myeloid, Acute pathology, Nucleophosmin, Prognosis, CD47 Antigen metabolism, Leukemia, Myeloid, Acute metabolism, Tissue Array Analysis
- Abstract
Binding of CD47 to signal regulatory protein alpha (SIRPα), an inhibitory receptor, negatively regulates phagocytosis. In acute myeloid leukemia (AML), CD47 is overexpressed on peripheral blasts and leukemia stem cells and inversely correlates with survival. Aim of the study was to investigate the correlation between CD47 protein expression by immunohistochemistry (IHC) in a bone marrow (BM) tissue microarray (TMA) and clinical outcome in AML patients. CD47 staining on BM leukemia blasts was scored semi-quantitatively and correlated with clinical parameters and known prognostic factors in AML. Low (scores 0-2) and high (score 3) CD47 protein expression were observed in 75% and 25% of AML patients. CD47 expression significantly correlated with percentage BM blast infiltration and peripheral blood blasts. Moreover, high CD47 expression was associated with nucleophosmin (NPM1) gene mutations. In contrast, CD47 expression did not significantly correlate with overall or progression free survival or response to therapy. In summary, a BM TMA permits rapid and reproducible semi-quantitative analysis of CD47 protein expression by IHC. While CD47 expression on circulating AML blasts has been shown to be a negative prognostic marker for a very defined population of AML patients with NK AML, CD47 expression on AML BM blasts is not., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
48. Regulation of hematopoietic and leukemic stem cells by the immune system.
- Author
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Riether C, Schürch CM, and Ochsenbein AF
- Subjects
- Humans, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells immunology, Immune System, Leukemia immunology, Neoplastic Stem Cells immunology, Stem Cell Niche immunology
- Abstract
Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4(+) and CD8(+) T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.
- Published
- 2015
- Full Text
- View/download PDF
49. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling.
- Author
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Balmer ML, Schürch CM, Saito Y, Geuking MB, Li H, Cuenca M, Kovtonyuk LV, McCoy KD, Hapfelmeier S, Ochsenbein AF, Manz MG, Slack E, and Macpherson AJ
- Subjects
- Adaptive Immunity, Adaptor Proteins, Vesicular Transport deficiency, Adaptor Proteins, Vesicular Transport genetics, Animals, Biological Evolution, Bone Marrow Cells immunology, Bone Marrow Cells microbiology, Gene Expression Regulation, Germ-Free Life, Immunity, Innate, Intestines immunology, Intestines microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells microbiology, Myeloid Differentiation Factor 88 deficiency, Myeloid Differentiation Factor 88 genetics, Myelopoiesis genetics, Adaptor Proteins, Vesicular Transport immunology, Antigens, Bacterial immunology, Microbiota immunology, Myeloid Cells immunology, Myeloid Differentiation Factor 88 immunology, Myelopoiesis immunology, Signal Transduction immunology
- Abstract
Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce "emergency granulopoiesis," the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88(-/-)TICAM1(-/-) mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
50. Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells.
- Author
-
Schürch CM, Riether C, and Ochsenbein AF
- Subjects
- Animals, Arenaviridae Infections immunology, Arenaviridae Infections virology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes virology, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Female, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells virology, Interferon-gamma pharmacology, Lymphocytic choriomeningitis virus pathogenicity, Male, Mesenchymal Stem Cells immunology, Mesenchymal Stem Cells virology, Mice, Mice, Inbred C57BL, Myeloid Cells cytology, Myeloid Cells immunology, Myeloid Cells virology, Signal Transduction, CD8-Positive T-Lymphocytes cytology, Cytokines metabolism, Hematopoiesis physiology, Hematopoietic Stem Cells cytology, Mesenchymal Stem Cells cytology, Myelopoiesis physiology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Cytotoxic CD8(+) T cells (CTLs) play a major role in host defense against intracellular pathogens, but a complete clearance of pathogens and return to homeostasis requires the regulated interplay of the innate and acquired immune systems. Here, we show that interferon γ (IFNγ) secreted by effector CTLs stimulates hematopoiesis at the level of early multipotent hematopoietic progenitor cells and induces myeloid differentiation. IFNγ did not primarily affect hematopoietic stem or progenitor cells directly. Instead, it promoted the release of hematopoietic cytokines, including interleukin 6 from bone marrow mesenchymal stromal cells (MSCs) in the hematopoietic stem cell niche, which in turn reduced the expression of the transcription factors Runx-1 and Cebpα in early hematopoietic progenitor cells and increased myeloid differentiation. Therefore, our study indicates that, during an acute viral infection, CTLs indirectly modulate early multipotent hematopoietic progenitors via MSCs in order to trigger the temporary activation of emergency myelopoiesis and promote clearance of the infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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