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1. Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways

Author

van Wigcheren, Glenn F., Cuenca-Escalona, Jorge, Stelloo, Suzan, Brake, Julia, Peeters, Eline, Horrevorts, Sophie.K., Frölich, Siebren, Ramos-Tomillero, Iván, Wesseling-Rozendaal, Yvonne, van Herpen, Carla M.L., van de Stolpe, Anja, Vermeulen, Michiel, de Vries, I. Jolanda M., Figdor, Carl G., and Flórez-Grau, Georgina

Published
2023
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2. Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients

Author

Van Wigcheren, Glenn F., De Haas, Nienke, Mulder, Tom A., Horrevorts, Sophie K., Bloemendal, Martine, Hins-Debree, Simone, Mao, Yumeng, Kiessling, Rolf, van Herpen, Carla M. L., Florez-Grau, Georgina, Hato, Stanleyson V., De Vries, I. Jolanda M., Van Wigcheren, Glenn F., De Haas, Nienke, Mulder, Tom A., Horrevorts, Sophie K., Bloemendal, Martine, Hins-Debree, Simone, Mao, Yumeng, Kiessling, Rolf, van Herpen, Carla M. L., Florez-Grau, Georgina, Hato, Stanleyson V., and De Vries, I. Jolanda M.

Abstract

Cancer immunotherapies have induced long-lasting responses in cancer patients including those with melanoma and head and neck squamous cell carcinoma (HNSCC). However, the majority of treated patients does not achieve clinical benefit from immunotherapy because of systemic tumor-induced immunosuppression. Monocytic myeloid-derived suppressor cells (M-MDSCs) are implicated as key players in inhibiting anti-tumor immune responses and their frequencies are closely associated with tumor progression. Tumor-derived signals, including signaling via STAT3-COX-2, induce the transformation of monocytic precursors into suppressive M-MDSCs. In a retrospective assessment, we observed that survival of melanoma patients undergoing dendritic cell vaccination was negatively associated with blood M-MDSC levels. Previously, it was shown that platinum-based chemotherapeutics inhibit STAT signaling. Here, we show that cisplatin and oxaliplatin treatment interfere with the development of M-MDSCs, potentially synergizing with cancer immunotherapy. In vitro, subclinical doses of platinum-based drugs prevented the generation of COX-2(+) M-MDSCs induced by tumor cells from melanoma patients. This was confirmed in HNSCC patients where intravenous cisplatin treatment drastically lowered M-MDSC frequency while monocyte levels remained stable. In treated patients, expression of COX-2 and arginase-1 in M-MDSCs was significantly decreased after two rounds of cisplatin, indicating inhibition of STAT3 signaling. In line, the capacity of M-MDSCs to inhibit activated T cell responses ex vivo was significantly decreased after patients received cisplatin. These results show that platinum-based chemotherapeutics inhibit the expansion and suppressive activity of M-MDSCs in vitro and in cancer patients. Therefore, platinum-based drugs have the potential to enhance response rates of immunotherapy by overcoming M-MDSC-mediated immunosuppression.

Published
2021
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4. Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients

Author

Van Wigcheren, Glenn F., primary, De Haas, Nienke, additional, Mulder, Tom A., additional, Horrevorts, Sophie K., additional, Bloemendal, Martine, additional, Hins-Debree, Simone, additional, Mao, Yumeng, additional, Kiessling, Rolf, additional, van Herpen, Carla M.L., additional, Flórez-Grau, Georgina, additional, Hato, Stanleyson V., additional, and De Vries, I. Jolanda M., additional

Published
2021
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5. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., Holmes, Mark A., Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., and Holmes, Mark A.

Published
2017

6. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

dFAH I&I, dFAH AVR, dI&I I&I-4, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J, Wagenaar, Jaap A, Klunder, Heleen M, Fitzgerald, J Ross, Zadoks, Ruth, Paterson, Gavin K, Torres, Carmen, Waller, Andrew S, Loeffler, Anette, Loncaric, Igor, Hoet, Armando E, Bergström, Karin, De Martino, Luisa, Pomba, Constança, de Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J, Chilvers, Edwin R, de Haas, Carla, van Kessel, Kok, van Strijp, Jos A G, Harrison, Ewan M, Holmes, Mark A, dFAH I&I, dFAH AVR, dI&I I&I-4, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J, Wagenaar, Jaap A, Klunder, Heleen M, Fitzgerald, J Ross, Zadoks, Ruth, Paterson, Gavin K, Torres, Carmen, Waller, Andrew S, Loeffler, Anette, Loncaric, Igor, Hoet, Armando E, Bergström, Karin, De Martino, Luisa, Pomba, Constança, de Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J, Chilvers, Edwin R, de Haas, Carla, van Kessel, Kok, van Strijp, Jos A G, Harrison, Ewan M, and Holmes, Mark A

Published
2017

7. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., Holmes, Mark A., MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M L, Lok, Laurence S C, Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nicholas, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ross, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, De Martino, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., Gosselaar-de Haas, CJC, van Kessel, CPM, Van Strijp, Jos A G, Harrison, Ewan M., and Holmes, Mark A.

Published
2017

8. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Koop, Gerrit, primary, Vrieling, Manouk, additional, Storisteanu, Daniel M. L., additional, Lok, Laurence S. C., additional, Monie, Tom, additional, van Wigcheren, Glenn, additional, Raisen, Claire, additional, Ba, Xiaoliang, additional, Gleadall, Nicholas, additional, Hadjirin, Nazreen, additional, Timmerman, Arjen J., additional, Wagenaar, Jaap A., additional, Klunder, Heleen M., additional, Fitzgerald, J. Ross, additional, Zadoks, Ruth, additional, Paterson, Gavin K., additional, Torres, Carmen, additional, Waller, Andrew S., additional, Loeffler, Anette, additional, Loncaric, Igor, additional, Hoet, Armando E., additional, Bergström, Karin, additional, De Martino, Luisa, additional, Pomba, Constança, additional, de Lencastre, Hermínia, additional, Ben Slama, Karim, additional, Gharsa, Haythem, additional, Richardson, Emily J., additional, Chilvers, Edwin R., additional, de Haas, Carla, additional, van Kessel, Kok, additional, van Strijp, Jos A. G., additional, Harrison, Ewan M., additional, and Holmes, Mark A., additional

Published
2017
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9. LukMF′ is the major secreted leukocidin of bovine Staphylococcus aureus and is produced in vivo during bovine mastitis

Author

Vrieling, Manouk, Boerhout, Eveline M., Van Wigcheren, Glenn F., Koymans, Kirsten J., Mols-Vorstermans, Tanja G., de Haas, Carla J C, Aerts, Piet C., Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P., Rutten, Victor P M G, Nuijten, Piet J M, Van Strijp, Jos A G, Benedictus, Lindert, Vrieling, Manouk, Boerhout, Eveline M., Van Wigcheren, Glenn F., Koymans, Kirsten J., Mols-Vorstermans, Tanja G., de Haas, Carla J C, Aerts, Piet C., Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P., Rutten, Victor P M G, Nuijten, Piet J M, Van Strijp, Jos A G, and Benedictus, Lindert

Published
2016

10. LukMF' is the major secreted leukocidin of bovine Staphylococcus aureus and is produced in vivo during bovine mastitis

Author

dFAH I&I, Vrieling, Manouk, Boerhout, Eveline M, van Wigcheren, Glenn F, Koymans, Kirsten J, Mols-Vorstermans, Tanja G, de Haas, Carla J C, Aerts, Piet C, Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P, Rutten, Victor P M G, Nuijten, Piet J M, van Strijp, Jos A G, Benedictus, Lindert, dFAH I&I, Vrieling, Manouk, Boerhout, Eveline M, van Wigcheren, Glenn F, Koymans, Kirsten J, Mols-Vorstermans, Tanja G, de Haas, Carla J C, Aerts, Piet C, Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P, Rutten, Victor P M G, Nuijten, Piet J M, van Strijp, Jos A G, and Benedictus, Lindert

Published
2016

11. LukMF′ is the major secreted leukocidin of bovine Staphylococcus aureus and is produced in vivo during bovine mastitis

Author

MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, CTI Borghans, Vrieling, Manouk, Boerhout, Eveline M., Van Wigcheren, Glenn F., Koymans, Kirsten J., Mols-Vorstermans, Tanja G., de Haas, Carla J C, Aerts, Piet C., Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P., Rutten, Victor P M G, Nuijten, Piet J M, Van Strijp, Jos A G, Benedictus, Lindert, MMB, UMC Utrecht, Infection & Immunity, MMB Research line 1, CTI Borghans, Vrieling, Manouk, Boerhout, Eveline M., Van Wigcheren, Glenn F., Koymans, Kirsten J., Mols-Vorstermans, Tanja G., de Haas, Carla J C, Aerts, Piet C., Daemen, Ineke J J M, van Kessel, Kok P M, Koets, Ad P., Rutten, Victor P M G, Nuijten, Piet J M, Van Strijp, Jos A G, and Benedictus, Lindert

Published
2016

12. LukMF′ is the major secreted leukocidin of bovine Staphylococcus aureus and is produced in vivo during bovine mastitis

Author

Vrieling, Manouk, primary, Boerhout, Eveline M., additional, van Wigcheren, Glenn F., additional, Koymans, Kirsten J., additional, Mols-Vorstermans, Tanja G., additional, de Haas, Carla J. C., additional, Aerts, Piet C., additional, Daemen, Ineke J. J. M., additional, van Kessel, Kok P. M., additional, Koets, Ad P., additional, Rutten, Victor P. M. G., additional, Nuijten, Piet J.M., additional, van Strijp, Jos A. G., additional, and Benedictus, Lindert, additional

Published
2016
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13. Potent in Vitroand In VivoEfficacy of BYON4413, a Duba-Based Antibody-Drug Conjugate Targeting CD123 in Acute Myeloid Leukemia

Author

van der Lee, Miranda, van Achtenberg, Tanja, Brouwers-Vos, Annet, van der Vleuten, Monique, Kappers, Wendy, Verheijden, Gijs, Huls, Geert A., van Wigcheren, Glenn, Ubink, Ruud, Sesink, Aloys, MacInnes, Alyson, Schuringa, Jan Jacob, and Dokter, Wim

Abstract

Acute myeloid leukemia (AML) and myelodysplasia (MDS) result from a differentiation impairment driving an accumulation of immature myeloid cells in the bone marrow and peripheral blood. A widely reported feature of these neoplastic myeloid cells is an increased cell surface expression of CD123, the IL3 receptor α subunit. This observation has established CD123 as an attractive target for precision therapy. Here, we describe BYON4413, a novel antibody-drug conjugate (ADC) that binds with high affinity to CD123. BYON4413 comprises a humanized IgG1 antibody directed at CD123 that is site-specifically conjugated to Byondis' proprietary duocarmazine linker-drug (LD) technology, ByonZine® and ByonShieLD®. This LD, when cleaved upon internalization and lysosomal routing, releases a potent duocarmycin payload that alkylates DNA, generating damage that results in replication stress and cell death. In vitrostudies with AML cell lines demonstrate that BYON4413 is highly effective in eradicating CD123-positive cells while having little impact on CD123-negative cells. Similar results are observed when we test BYON4413 on AML patient-derived BMMCs/PBMCs in ex vivoassays (n=50), indicating that the specificity of BYON4413 cytotoxicity is largely limited to CD123-positive cells. Ex vivoexperiments also reveal a stronger potency of BYON4413 in AML patient-derived blasts compared to healthy CD34 +hematopoietic stem/progenitor cells. In vivoPK/PD studies demonstrate that BYON4413 is remarkably efficient at reducing the tumor burden in multiple AML patient- and cell line-derived xenograft models. Studies in non-human primates suggest that BYON4413 has a favorable toxicity profile and a high maximum tolerable dose, features that should enable combination strategies with other oncolytics. In sum, BYON4413 shows great potential to be an effective targeted therapy against AML, MDS, and other CD123 +hematological malignancies such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Readied with these promising pre-clinical results, we have designed a first-in-human dose-escalation and expansion trial enrolling AML and high-risk MDS patients scheduled to begin in Q12024.

Published
2023
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14. Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Author

Andrew S. Waller, Igor Loncaric, Jaap A. Wagenaar, Luisa De Martino, Haythem Gharsa, Jos A. G. van Strijp, Emily J. Richardson, Nicholas Gleadall, Carmen Torres, Laurence Si Lok, Arjen J. Timmerman, Armando E. Hoet, Ewan M. Harrison, Tom P. Monie, Constança Pomba, Carla J. C. de Haas, Xiaoliang Ba, Anette Loeffler, Gerrit Koop, Mark A. Holmes, Edwin R. Chilvers, Gavin K. Paterson, Heleen M Klunder, Hermínia de Lencastre, Ruth N. Zadoks, Manouk Vrieling, Claire Raisen, Karin Bergström, J. Ross Fitzgerald, Kok P. M. van Kessel, Glenn F van Wigcheren, Daniel M. L. Storisteanu, Nazreen F. Hadjirin, Karim Ben Slama, Lok, Laurence [0000-0002-9364-4213], Monie, Tom [0000-0003-4097-1680], Ba, Xiaoliang [0000-0002-3882-3585], Chilvers, Edwin [0000-0002-4230-9677], Harrison, Ewan [0000-0003-2720-0507], Holmes, Mark [0000-0002-5454-1625], Apollo - University of Cambridge Repository, Koop, Gerrit, Vrieling, Manouk, Storisteanu, Daniel M. L., Lok, Laurence S. C., Monie, Tom, Van Wigcheren, Glenn, Raisen, Claire, Ba, Xiaoliang, Gleadall, Nichola, Hadjirin, Nazreen, Timmerman, Arjen J., Wagenaar, Jaap A., Klunder, Heleen M., Fitzgerald, J. Ro, Zadoks, Ruth, Paterson, Gavin K., Torres, Carmen, Waller, Andrew S., Loeffler, Anette, Loncaric, Igor, Hoet, Armando E., Bergström, Karin, DE MARTINO, Luisa, Pomba, Constança, De Lencastre, Hermínia, Ben Slama, Karim, Gharsa, Haythem, Richardson, Emily J., Chilvers, Edwin R., De Haas, Carla, Van Kessel, Kok, Van Strijp, Jos A. G., Harrison, Ewan M., Holmes, Mark A., dFAH I&I, dFAH AVR, and dI&I I&I-4

Subjects
0301 basic medicine, Neutrophils, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Cell, HUMAN C5A RECEPTORS, Leukocidin, Host tropism, PROTEIN, Plasma protein binding, medicine.disease_cause, LYMPHOCYTES, Receptors, Interleukin-8B, Leukocidins, BINDING, Gene Order, CHEMOKINE RECEPTORS, GAMMA-HEMOLYSIN, Receptor, Phylogeny, Multidisciplinary, Bacteriologie, Bacteriology, Host Pathogen Interaction & Diagnostics, Staphylococcal Infections, Multidisciplinary Sciences, medicine.anatomical_structure, Staphylococcus aureus, Science & Technology - Other Topics, BOVINE, Pathogens, Protein Binding, Cell Survival, 030106 microbiology, Bacterial Toxins, Phage biology, Biology, Staphylococcal infections, LEUKOTOXIN, Article, Host Specificity, Microbiology, 03 medical and health sciences, PANTON-VALENTINE LEUCOCIDIN, Journal Article, medicine, Life Science, Animals, Humans, Horses, General, Prophage, Host Pathogen Interaction & Diagnostics, Science & Technology, Bacteriology, medicine.disease, Host Pathogen Interactie & Diagnostiek, 030104 developmental biology, Bacteriologie, Host Pathogen Interactie & Diagnostiek, Cattle, Horse Diseases
Abstract

Contains fulltext : 177770.pdf (Publisher’s version ) (Open Access) Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (PhiSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.

Published
2017
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