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Article: TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems.

Alizadeh Zeinabad, Hojjat / Szegezdi, Eva

2022 Volume 14, Issue 20

Abstract: The death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine superfamily, has long been recognized for its potential as a cancer therapeutic due to its low toxicity against normal cells. However, ... ...

Abstract	The death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine superfamily, has long been recognized for its potential as a cancer therapeutic due to its low toxicity against normal cells. However, its translation into a therapeutic molecule has not been successful to date, due to its short in vivo half-life associated with insufficient tumor accumulation and resistance of tumor cells to TRAIL-induced killing. Nanotechnology has the capacity to offer solutions to these limitations. This review provides a perspective and a critical assessment of the most promising approaches to realize TRAIL's potential as an anticancer therapeutic, including the development of fusion constructs, encapsulation, nanoparticle functionalization and tumor-targeting, and discusses the current challenges and future perspectives.
Language	English
Publishing date	2022-10-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14205125
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Article ; Online: CCPlotR: an R package for the visualization of cell-cell interactions.

Ennis, Sarah / Ó Broin, Pilib / Szegezdi, Eva

Bioinformatics advances

2023 Volume 3, Issue 1, Page(s) vbad130

Abstract: Summary: We present CCPlotR-an R package that generates visualizations of cell-cell interactions. CCPlotR is designed to work with the output of tools that predict cell-cell interactions from single-cell gene expression data and requires only a table of ...

Abstract	Summary: We present CCPlotR-an R package that generates visualizations of cell-cell interactions. CCPlotR is designed to work with the output of tools that predict cell-cell interactions from single-cell gene expression data and requires only a table of predicted interactions as input. The package can generate a comprehensive set of publication-ready figures such as heatmaps, dotplots, circos plots and network diagrams, providing a useful resource for researchers working on cell-cell interactions. Availability and implementation: CCPlotR is available to download and install from GitHub (https://github.com/Sarah145/CCPlotR) and comes with a toy dataset to demonstrate the different functions. Support for users will be provided via the GitHub issues tracker (https://github.com/Sarah145/CCPlotR/issues).
Language	English
Publishing date	2023-09-20
Publishing country	England
Document type	Journal Article
ISSN	2635-0041
ISSN (online)	2635-0041
DOI	10.1093/bioadv/vbad130
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Article ; Online: Editorial: Death Receptors, Non-apoptotic Signaling Pathways and Inflammation.

Szegezdi, Eva / Legembre, Patrick

Frontiers in immunology

2020 Volume 11, Page(s) 2162

MeSH term(s)	Animals ; Apoptosis ; Humans ; Inflammation/metabolism ; NF-kappa B/metabolism ; Receptors, Death Domain/metabolism ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Signal Transduction
Chemical Substances	NF-kappa B ; Receptors, Death Domain ; Receptors, Tumor Necrosis Factor, Type I
Language	English
Publishing date	2020-09-08
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.02162
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Article ; Online: Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities.

O'Reilly, Eimear / Zeinabad, Hojjat Alizadeh / Szegezdi, Eva

Blood reviews

2021 Volume 50, Page(s) 100850

Abstract: Hematopoietic stem cells (HSC) are responsible for the production of mature blood cells. To ensure that the HSC pool does not get exhausted over the lifetime of an individual, most HSCs are in a state of quiescence with only a small proportion of HSCs ... ...

Abstract	Hematopoietic stem cells (HSC) are responsible for the production of mature blood cells. To ensure that the HSC pool does not get exhausted over the lifetime of an individual, most HSCs are in a state of quiescence with only a small proportion of HSCs dividing at any one time. HSC quiescence is carefully controlled by both intrinsic and extrinsic, niche-driven mechanisms. In acute myeloid leukemia (AML), the leukemic cells overtake the hematopoietic bone marrow niche where they acquire a quiescent state. These dormant AML cells are resistant to chemotherapeutics. Because they can re-establish the disease after therapy, they are often termed as quiescent leukemic stem cells (LSC) or leukemia-initiating cells. While advancements are being made to target particular driver mutations in AML, there is less focus on how to tackle the drug resistance of quiescent LSCs. This review summarises the current knowledge on the biochemical characteristics of quiescent HSCs and LSCs, the intracellular signaling pathways and the niche-driven mechanisms that control quiescence and the key differences between HSC- and LSC-quiescence that may be exploited for therapy.
MeSH term(s)	Bone Marrow/physiology ; Hematopoietic Stem Cells/physiology ; Humans ; Leukemia, Myeloid, Acute ; Neoplastic Stem Cells/drug effects ; Signal Transduction/genetics ; Signal Transduction/physiology
Language	English
Publishing date	2021-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639015-8
ISSN	1532-1681 ; 0268-960X
ISSN (online)	1532-1681
ISSN	0268-960X
DOI	10.1016/j.blre.2021.100850
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Article ; Online: Macromolecular crowding in the development of a three-dimensional organotypic human breast cancer model.

Shologu, Naledi / Gurdal, Mehmet / Szegezdi, Eva / FitzGerald, Una / Zeugolis, Dimitrios I

Biomaterials

2022 Volume 287, Page(s) 121642

Abstract: Although cell-derived matrices are at the forefront of scientific research and technological innovation for the development of in vitro tumour models, their two-dimensional structure and low extracellular matrix composition restrict their capacity to ... ...

Abstract	Although cell-derived matrices are at the forefront of scientific research and technological innovation for the development of in vitro tumour models, their two-dimensional structure and low extracellular matrix composition restrict their capacity to accurately predict toxicity of candidate molecules. Herein, we assessed the potential of macromolecular crowding (a biophysical phenomenon that significantly enhances and accelerates extracellular matrix deposition, resulting in three-dimensional tissue surrogates) in improving cell-derived matrices in vitro tumour models. Among the various decellularisation protocols assessed (NH
Language	English
Publishing date	2022-06-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2022.121642
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Article ; Online: Generation of Tumour-stroma Minispheroids for Drug Efficacy Testing.

Watters, Mark / Szegezdi, Eva

Bio-protocol

2017 Volume 7, Issue 1, Page(s) e2091

Abstract: The three-dimensional organisation of cells in a tissue and their interaction with adjacent cells and extracellular matrix is a key determinant of cellular responses, including how tumour cells respond to stress conditions or therapeutic drugs (Elliott ... ...

Abstract	The three-dimensional organisation of cells in a tissue and their interaction with adjacent cells and extracellular matrix is a key determinant of cellular responses, including how tumour cells respond to stress conditions or therapeutic drugs (Elliott and Yuan, 2011).
Language	English
Publishing date	2017-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.2091
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Article ; Online: Natural killer cell-mimic nanoparticles can actively target and kill acute myeloid leukemia cells.

Alizadeh Zeinabad, Hojjat / Yeoh, Wen Jie / Arif, Maryam / Lomora, Mihai / Banz, Yara / Riether, Carsten / Krebs, Philippe / Szegezdi, Eva

Biomaterials

2023 Volume 298, Page(s) 122126

Abstract: Natural killer (NK) cells play a crucial role in recognizing and killing emerging tumor cells. However, tumor cells develop mechanisms to inactivate NK cells or hide from them. Here, we engineered a modular nanoplatform that acts as NK cells (NK cell- ... ...

Abstract	Natural killer (NK) cells play a crucial role in recognizing and killing emerging tumor cells. However, tumor cells develop mechanisms to inactivate NK cells or hide from them. Here, we engineered a modular nanoplatform that acts as NK cells (NK cell-mimics), carrying the tumor-recognition and death ligand-mediated tumor-killing properties of an NK cell, yet without being subject to tumor-mediated inactivation. NK cell mimic nanoparticles (NK.NPs) incorporate two key features of activated NK cells: cytotoxic activity via the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and an adjustable tumor cell recognition feature based on functionalization with the NK cell Fc-binding receptor (CD16, FCGR3A) peptide, enabling the NK.NPs to bind antibodies targeting tumor antigens. NK.NPs showed potent in vitro cytotoxicity against a broad panel of cancer cell lines. Upon functionalizing the NK.NPs with an anti-CD38 antibody (Daratumumab), NK.NPs effectively targeted and eliminated CD38-positive patient-derived acute myeloid leukemia (AML) blasts ex vivo and were able to target and kill CD38-positive AML cells in vivo, in a disseminated AML xenograft system and reduced AML burden in the bone marrow compared to non-targeted, TRAIL-functionalized liposomes. Taken together, NK.NPs are able to mimicking key antitumorigenic functions of NK cells and warrant their development into nano-immunotherapeutic tools.
MeSH term(s)	Humans ; Ligands ; Killer Cells, Natural ; Leukemia, Myeloid, Acute/drug therapy ; Apoptosis ; Tumor Necrosis Factor-alpha ; Nanoparticles ; Cytotoxicity, Immunologic
Chemical Substances	Ligands ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-04-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2023.122126
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Article ; Online: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content.

Gunalp, Sinem / Helvaci, Derya Goksu / Oner, Aysenur / Bursalı, Ahmet / Conforte, Alessandra / Güner, Hüseyin / Karakülah, Gökhan / Szegezdi, Eva / Sag, Duygu

Frontiers in immunology

2023 Volume 14, Page(s) 1209249

Abstract: Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent ... ...

Abstract	Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known. Methods: Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes Results: TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells Conclusions: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.
MeSH term(s)	Humans ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Macrophages/metabolism ; Phenotype ; RNA, Messenger/metabolism ; Receptors, Death Domain/metabolism ; Leukemia, Myeloid, Acute/metabolism ; Tumor Microenvironment
Chemical Substances	TNF-Related Apoptosis-Inducing Ligand ; RNA, Messenger ; Receptors, Death Domain
Language	English
Publishing date	2023-09-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1209249
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Article ; Online: Guiding the Killer and Bringing in Accomplices: Bispecific Antibody Treatment for Malignant Melanoma.

Szegezdi, Eva / Leverkus, Martin

The Journal of investigative dermatology

2016 Volume 136, Issue 2, Page(s) 362–364

Abstract: Discovery of oncogene and immune checkpoint targeting has transformed melanoma therapy in the last 5 years. However, treatment of primary or secondary drug-resistant melanoma remains a challenge. Agents designed to activate the cell death machinery ... ...

Abstract	Discovery of oncogene and immune checkpoint targeting has transformed melanoma therapy in the last 5 years. However, treatment of primary or secondary drug-resistant melanoma remains a challenge. Agents designed to activate the cell death machinery directly, for example by activating the death receptors expressed by melanoma cells, could break drug resistance, and they may achieve long-lasting therapeutic success. He et al. report their studies of an MCSPxDR5 bispecific, tetravalent antibody that can simultaneously target death receptor 5 (DR5, TRAIL-R2) and melanoma-associated chondroitin sulfate proteoglycan (MCSP). This antibody can exert strong and selective DR5-dependent cytotoxic activity against MCSP-expressing melanoma cells. Crosslinking of the antibody with Fcγ-receptors increased the cytotoxic potential further, without compromising its selectivity. This approach offers a novel immunotherapeutic tool via coupling of three cooperating processes: delivering the death receptor agonist to the malignant cell population, potent activation of DR5-mediated cell death signaling, and recruitment of Fcγ-receptor-carrying immune cells that can mount an immune response against the tumor cells.
MeSH term(s)	Apoptosis/immunology ; Humans ; Mitochondrial Proteins/immunology ; Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology
Chemical Substances	Mitochondrial Proteins ; Receptors, TNF-Related Apoptosis-Inducing Ligand
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2015.12.002
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Article ; Online: Cell-cell interactome of the hematopoietic niche and its changes in acute myeloid leukemia.

Ennis, Sarah / Conforte, Alessandra / O'Reilly, Eimear / Takanlu, Javid Sabour / Cichocka, Tatiana / Dhami, Sukhraj Pal / Nicholson, Pamela / Krebs, Philippe / Ó Broin, Pilib / Szegezdi, Eva

iScience

2023 Volume 26, Issue 6, Page(s) 106943

Abstract: The bone marrow (BM) is a complex microenvironment, coordinating the production of billions of blood cells every day. Despite its essential role and its relevance to hematopoietic diseases, this environment remains poorly characterized. Here we present a ...

Abstract	The bone marrow (BM) is a complex microenvironment, coordinating the production of billions of blood cells every day. Despite its essential role and its relevance to hematopoietic diseases, this environment remains poorly characterized. Here we present a high-resolution characterization of the niche in health and acute myeloid leukemia (AML) by establishing a single-cell gene expression database of 339,381 BM cells. We found significant changes in cell type proportions and gene expression in AML, indicating that the entire niche is disrupted. We then predicted interactions between hematopoietic stem and progenitor cells (HSPCs) and other BM cell types, revealing a remarkable expansion of predicted interactions in AML that promote HSPC-cell adhesion, immunosuppression, and cytokine signaling. In particular, predicted interactions involving transforming growth factor β1 (TGFB1) become widespread, and we show that this can drive AML cell quiescence
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106943
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