Thesis defense Thanos Blanas

Last Tuesday 12th of January Thanos Blanas of the group of Sandra van Vliet successfully defended his thesis entitled ”Aberrant cancer glycosylation: a potent regulator of tumor growth and anti-tumor immunity”.

Sue Gibbs

About

Sue Gibbs is professor in Skin and Mucosa Regenerative Medicine. She is PI at the Department of Molecular Cell Biology & Immunology and also in the Department of Oral Cell Biology, ACTA. Her entire career has focused on animal alternative methods, in particular in developing human healthy and disease models drug discovery, pre-clinical studies and safety testing. She combines cutting-edge research in cell biology and immunology with advances in tissue engineering. Current focus lies with developing next generation immune competent tissue engineered constructs to investigate the (patho)physiology of adverse scar formation and to investigate similarities and differences between tolerance, allergic and irritant contact dermatitis with the aim of identifying novel drug targets for personalized as well as general therapeutic strategies. Recently, her research has extended into the field of hair follicles and importantly ‘’organ-on-a-chip’’, in particular immune competent skin-, gingiva-, gut,- lymph node- and melanoma- “on-chip”. Sue Gibbs was awarded numerous grants from EU, NWO, TTW, Dutch Burns foundation, in collaboration with partners from industry.

Research Line

Human healthy and disease model technologies: Immune competent Skin-on-Chip for risk assessment and cancer research: NextSkin project

Our aim is to develop the next generation immune competent human skin models which closely represent healthy and diseased skin, thus providing a platform for safety and efficacy testing of drugs and consumer products which come into contact with our skin. Our focus is on fibrosis, cancer, allergy and tolerance.  Cell types which can currently be built into our organotypic models include epithelial cells (keratinocytes, melanocytes, Langerhans cells, melanoma), dermal cells (fibroblasts, myofibroblasts, hair follicles, blood and lymph vessel endothelial cells, dendritic cells, monocytes, macrophages) and adipose tissue cells (mesenchymal stromal cells, adipocytes and endothelial cells). These models are being incorporated into micro-physiological bioreactors, ‘’organ-on-a-chip’’, to create immune competent skin-, gingiva-, gut,- lymph node- and melanoma- “on-chip”.

Inflammatory skin and oral mucosa disease

Research is aimed at identifying the mechanisms involved in skin and oral soft tissue homeostasis and inflammation. Examples of our research questions include: why does a deep skin wound heal with a bad scar formation whilst oral wounds heal with relatively little scar? Is this to do with intrinsic properties of the cells or is this due to extrinsic factors e.g.: saliva, microbiome? With the aid of normal skin / gingival equivalents, and in vitro hypertrophic scar and keloid scar equivalents the mechanisms of scar formation can be investigated. Another major research question is: why does first contact with an allergen (e.g. Nickel) via the skin often result in sensitization whereas first contact via the mouth with the same allergen results in tolerance? With the aid of skin and gingival equivalents containing integrated Langerhans Cells, innate and adaptive mechanisms involved in sensitization versus tolerance and pathogen infection are being investigated.

Key publications

  1. Shang, L., et al., Commensal and Pathogenic Biofilms Alter Toll-Like Receptor Signaling in Reconstructed Human Gingiva. Front Cell Infect Microbiol. 2019 Aug 7;9:282. doi: 10.3389/fcimb.2019.00282. eCollection 2019
  2. Limandjaja, G.C., et al., Characterization of In Vitro Reconstructed Human Normotrophic, Hypertrophic, and Keloid Scar Models. Tissue Eng Part C Methods, 2018. 24(4): p. 242-253.
  3. Monsuur, H.N., et al., Endothelial cells enhance adipose mesenchymal stromal cell-mediated matrix contraction via ALK receptors and reduced follistatin: Potential role of endothelial cells in skin fibrosis. J Cell Physiol. 2018 Oct;233(10):6714-6722. doi: 10.1002/jcp.26494. Epub 2018
  4. Bil, W., et al., Comparison of the skin sensitization potential of 3 red and 2 black tattoo inks using interleukin-18 as a biomarker in a reconstructed human skin model. Contact Dermatitis, 2018. 79(6): p. 336-345.
  5. Kosten, I.J., et al., MUTZ-3 derived Langerhans cells in human skin equivalents show differential migration and phenotypic plasticity after allergen or irritant exposure. Appl. Pharmacol, 2015. 287(1): p. 35-42.

Group members

Andrew Morrison

Andrew Morrison, MSc

PhD student
My project aims to develop a functional 3D organotypic lymph node with integrated lymphatics that mimic adaptive immune responses. Combining research on lymph node stromal cells and current in-house expertise of tissue engineering & microfluidic devices, the overall objective of the project is to design an organ-on-chip model that features lymphatic drainage of an immune competent gut into a lymph node. The immunosurveillance capability of the model will then be assessed by inducing an inflammatory response, leading to its availability as a future platform for rheumatoid arthritis drug testing.

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Elisabetta Michielon, MSc

PhD student
My project focuses on developing an organotypic three-dimensional in vitro metastatic melanoma-in-skin model to study disease development and progression, as well as in situ tumor-induced immune suppression. The incorporation of immune cells into the model and its further integration into a microfluidic device will provide a valuable tool for the testing of immunotherapies in a relevant human setting. To this aim and to unravel features of the melanoma model, I mostly use tissue engineering in combination with cytokine ELISAs, immunohistochemistry, and flow cytometry.

Ibrahim Korkmaz

H. Ibrahim Korkmaz, PhD

Postdoctoral researcher
Treating patients with severe burns and understanding the mechanisms involved, which can lead to improved treatment strategies, is very complex. The aim of my project is the development, optimization and standardization of a 3D (printed) reconstructed human skin model for burn wound healing. Moreover, I am working on a totally new approach which is complementary to organotypic skin models which are used to investigate wound healing and fibrosis: it is a systems biology approach to understanding burn wound healing.

Jasper Koning

Jasper Koning, PhD

Postdoctoral researcher
My works focuses on developing complex in vitro human metabolically and immune competent skin model connected to microfluidics vasculature in a skin on a chip format. This model can be used for experimental research, testing of compounds as well as drug discovery.

JonasJäger_passphoto

Jonas Jäger, MSc

PhD student
• I have a strong interest in tissue engineering. We are constructing metabolically active and immune competent skin equivalents with the aim to reduce animal testing for the safety assessment of drugs and chemicals. Therefore, we use multi-organ-chips (or so called microphysiological systems), bioprinting and various analysis methods such as immunohistochemistry, RNA sequencing, cytokine ELISAs, (3D-)microscopy and toxicity assays.

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Lin Shang, PhD

postdoctoral researcher
My project is about developing a host-microbe interaction model using reconstructed human gingiva and multi-species oral biofilms to mimic the native situation in the oral cavity. With this model we aim to study how the oral host-microbe interactions correlate with oral health and disease, using techniques such as (immune)histochemical staining, ELISAs, 16S rRNA sequencing, metabolic assays.

Maaike Waasdorp

Maaike Waasdorp, PhD

Postdoctoral researcher
Using reconstructed human skin and oral mucosa cultures, my aim is to find host-microbiome interactions that contribute to superial oral wound healing and to identify therapeutic targets for promoting optimal healing of burn wounds.

Maria_Thon

Maria Thon, Ing

senior research technician
My expertise is in culturing reconstructed human skin models for many different research questions. I am specialized in skin, hair, endothelial cell, adipose tissue isolation and culture. Detection techniques: IHC (also fluorescence), ELISA , WB, qPCR. I have experience with good laboratory practice (GLP), cleanroom production (GMP) of skin constructs for chronic wounds and burns, METC and Kwaliteitsnet. Currently I am working on the NextSkin project.

Melis Asal

Melis Asal, MSc

PhD student
The focus of my work is developing an immune competent organotypic Gut-on-Chip model capable of immune surveillance. The model will be used for mimicking the effect of microbiome, testing immune responses and uptake of orally digested drugs for rheumatoid arthritis.

Sander Spiekstra

Sander W. Spiekstra, BSc

Operator / Senior technician
My entire career has focussed on the refinement and replacement of animal models to perform risk assessment on chemicals which may potentially cause an irritant or allergenic reaction in skin. The immune defence system of the skin has my greatest interest . As operator and specialist in the culturing of 3D immunocompetent skin equivalents with Langerhans Cells and Dendritic Cells, i am responsible for theoretical and technical assistance in these research lines . As one of the operators of the Attune flow cytometer and member of MCCF (microscopy and flow facility) i am happy to assist with flow cytometry experiments on this machine. (3D) Tissue culturing, Microscopy (light and fluorescence), Flow cytometry, RT-PCR (RNA profiling), protein arrays , Elisa, are techniques i use for my research. I am the “business information manager” for the statistical analysis program Graphpad. I am more than average trained to answer statistical questions. I serve as a contact person between the polyclinic Dermatology / Allergology in the location AMC and am trained in performing contract research for industrial partners. Also the maintenance of laboratory devices is one of my tasks in the lab.

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Sanne Roffel, Ing

Research technician
I’m a research technician so have been working on a lot of different projects and still do. Have a lot experience in culturing reconstructed human skin and gingiva models. These models are made with primary cells as well as with cell lines (ML II lab). These models are used for a wide spectrum of experiments. Like, wound healing questions properties, chemical exposures, implant attachment etc. To analyze the cultures I can use a lot of different techniques like, IHC (also Fluorescence), hard tissue embedding, FISH, ELISA, FACS and PCR. But also have some knowledge of the analytical techniques: HPLC and CE.

Stephanie Beekhuis-Hoekstra

Stephanie Beekhuis-Hoekstra, MSc

Researcher
My goal within the SkinLab is to generate high quality induced pluripotent stem cells from various donors that will be freely available to colleagues. Using these iPSCs, I also aim to improve existing in vitro animal-free skin models by the incorporation of appendages that are currently lacking, especially hair follicles. The generation of such a model will improve the predicatbility of compound screening and disease modeling, which we hope will eliminate the need for animal testing.

Taco Waaijman

Taco Waaijman, MSc

Research technician
My research focus on culturing of different kind of 3D skin- and gingiva-models, in combination with Organon-a-chip systems.

Other PI's

Gijs Kooij

About

Gijs Kooij is a PI (assistant professor) at the Department of Molecular Cell Biology & Immunology as well as the MS center Amsterdam. His main research focus is to understand the natural process to resolve neuro-inflammation in order to provide new perspectives on the pathogenesis of chronic (unresolved) neuro-inflammatory diseases like multiple sclerosis (MS) and to reveal new treatment opportunities. He recently discovered endogenous lipid mediator circuits in the central nervous system (CNS) and revealed the absence of protective lipid mediators in various disease stages of MS. These findings in combination with personal Vidi (NWO) and Fellowship (Dutch MS society) grants have enabled him to establish his own research group on inflammation-resolution mechanisms in health and disease.

Research Line

(Re)solving MS: Understand and exploit endogenous protection mechanisms.

Inflammation is a host-protective response when properly orchestrated. Beside immune checkpoints, the inflammatory cascade boasts an additional checkpoint, driven by chemical lipid mediators that induce resolution of inflammation. These novel autacoids, called specialized pro-resolving lipid mediators (SPMs), not only inhibit the inflammatory response, they also actively terminate it, leading to the restoration of tissue homeostasis. Novel sensitive detection methods (i.e. lipidomics) have set the stage to identify and decode these SPMs, which opens new perspectives on the pathogenesis of chronic (unresolved) inflammatory diseases like multiple sclerosis (MS).

By using a state-of-the-art lipidomics and mass-spectrometry imaging approach in combination with primary cell cultures, ex vivo brain slice cultures, in vivo neuro-inflammation models and human post-mortem tissues, we will elucidate in the coming years how altered inflammation-resolving mechanisms underlie MS pathogenesis by investigating both fundamental (Vidi) and clinical (fellowship) aspects. His ultimate goal is to provide novel diagnostic, prognostic and therapeutic opportunities for MS and other chronic (neuro-)inflammatory diseases based on resolution pharmacology (Figure 1).

Figure. Decision paths during neuro-inflammation: chronicity or resolution?
An effectively mounted inflammatory response will also trigger the activation of protective resolution pathways intended to safely terminate the inflammatory cascade and promote healing (1). Failed resolution can extend in time the actions of pro-inflammatory mechanisms resulting in prolonged (chronic) inflammation (2). I here propose that activation of endogenous circuits of resolution through novel resolution-based therapeutics (SPMs) can restore tissue structure and function to return to homeostasis (3).

Key publications

  1. Bogie J.F, Haidar M, Hendriks J.J.A and Kooij G. Fatty acid metabolism in the progression and resolution of CNS disorders. Advanced Drug Delivery Reviews. Conditionally accepted
  2. Derada Troletti C, Enzmann G, Chiurchiù V, Haghayegh N, Tietz S, Norris PC, van der Pol SMA, Serhan CN, de Vries HE, Engelhardt B and Kooij G. Pro-resolving lipid mediator Lipoxin A4 attenuates neuro-inflammation by modulating T cell responses and modifying the spinal cord lipidome. Cell Reports. Conditionally accepted.
  3. Kooij G, Derada Troletti C, Leuti A, Norris PC, Riley I, Albanese M, Ruggieri S, Libreros S, van der Pol SMA, van Het Hof B, Schell Y, Guerrera G, Buttari F, Mercuri NB, Centonze D, Gasperini C, Battistini L, de Vries HE, Serhan CN, Chiurchiù V. Specialized pro-resolving lipid mediators are differentially altered in peripheral blood of patients with multiple sclerosis and attenuate monocyte and blood-brain barrier dysfunction. Haematologica. 2019 Nov 28. pii: haematol.2019.219519. doi: 10.3324/haematol.2019.219519
  4. Kooij G, Kopplin K, Blasig R, Stuiver M, Koning N, Goverse G, van der Pol SM, van Het Hof B, Gollasch M, Drexhage JA, Reijerkerk A, Meij IC, Mebius R, Willnow TE, Müller D, Blasig IE, de Vries HE. Disturbed function of the blood-cerebrospinal fluid barrier aggravates neuro-inflammation. Acta Neuropathol. 2014 Aug 128(2): 267-77
  5. Kooij G, Kroon J, Paul D, Reijerkerk A, Geerts D, van der Pol SM, van Het Hof B, Drexhage JA, van Vliet SJ, Hekking LH, van Buul JD, Pachter JS, de Vries HE. P-glycoprotein regulates trafficking of CD8+ T cells to the brain parenchyma. Acta Neuropathol. 2014 May;127(5): 699-7112Aleyd E, van Hout MW, Ganzevles SH, Hoeben KA, Everts V, Bakema JE, van Egmond M. IgA enhances NETosis and release of neutrophil extracellular traps by polymorphonuclear cells via Fcα receptor I. J Immunol. 2014 Mar 1;192(5):2374-83.

Group members

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NAME, titles

JOB DESCRIPTION
RESEARCH DESCRIPTION

Other PI's

Elga de Vries

Research Line

Neuro-immunology: The neurovascular unit in health and disease                  

Altered activation of the immune system, neuroinflammation (marked by activated astrocytes and microglia), and dysfunction of the neuro-protective brain barriers are pathological hallmarks of many neurodegenerative disorders, such as multiple sclerosis (MS), various forms of dementia, including Alzheimer’s disease (AD),  and stroke. It becomes increasingly clear that chronic neuroinflammation, an altered immune response and neurovascular dysfunction may even be causal for onset and progression of such cognitive disorders, but underlying mechanisms remain unknown. The translational research of the De Vries group is therefore focused on understanding how alterations at the level of the immune system and the brain barriers underlie neuroinflammatory and neurodegenerative conditions.  In the current research, we aim to define underlying pathways that initiate neuro-inflammation as potential targets for treatment and identify if such alterations may serve as biomarkers for disease in well-defined patient cohorts. A better understanding of such pathological processes may in future not only lead to new diagnostic tools that reflect ongoing neuro-inflammation and brain barrier dysfunction, but may also lead to potential novel intervention strategies to fight neurogical disorders.

Key publications

  1. Wouters E, de Wit NM, Vanmol J, van der Pol SMA, van Het Hof B, Sommer D, Loix M, Geerts D, Gustafsson JA, Steffensen KR, Vanmierlo T, Bogie JFJ, Hendriks JJA, de Vries HE. Liver X Receptor Alpha Is Important in Maintaining Blood-Brain Barrier Function. Front Immunol. 2019;10:1811
  2. Derada Troletti C, Fontijn RD, Gowing E, Charabati M, van Het Hof B, Didouh I, van der Pol SMA, Geerts D, Prat A, van Horssen J, Kooij G, de Vries HE. Inflammation-induced endothelial to mesenchymal transition promotes brain endothelial cell dysfunction and occurs during multiple sclerosis pathophysiology. Cell Death Dis. 2019 18;10(2):45
  3. Chakraborty A, Kamermans A, van Het Hof B, Castricum K, Aanhane E, van Horssen J, Thijssen VL, Scheltens P, Teunissen CE, Fontijn RD, van der Flier WM, de Vries HE. Angiopoietin like-4 as a novel vascular mediator in capillary cerebral amyloid angiopathy. 2018 1;141(12):3377-3388.
  4. Kamermans A, Planting KE, Jalink K, van Horssen J, de Vries HE. Reactive astrocytes in multiple sclerosis impair neuronal outgrowth through TRPM7-mediated chondroitin sulfate proteoglycan production. Glia. 2019;67(1):68-77.
  5. Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, Windhorst AD, de Vries HE. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J Neuroinflammation. 2017 22;14(1):259

Group members

Hannah van der Stok

Hannah van der Stok, MSc

Research technician
My work focuses on blood brain barrier functioning. I am specifically interested in a protein named FHL2, which potentially plays a role in blood brain barrier dysfunction. Intracellular mechanisms involved in this process are investigated using in vitro models with lentiviral modifications and various molecular assays.

Inge Mulder

Inge Mulder, PhD

Senior postdoctoral researcher
My research is focused on the inaccurate reperfusion of the microvasculature of the brain, after recanalization therapy (thrombolysis or thrombectomy) in acute ischemic stroke. I aim to unravel underlying pathophysiological mechanisms of this phenomenon in order to find new therapeutic strategies to improve treatment efficacy. To do this, I use a translational approach including pre-clinical in-vivo 2-photon microscopy, MRI and Mass spectrometry as well as clinical data.

Lynn van Olst

Lynn van Olst, MSc

PhD Student
My research focusses on the (neuro)immunological processes that underlie Alzheimer's disease, MS and aging. For this purpose I utilize single-cell mass cytometry (CyTOF) and confocal imaging. Microglia and T cells are my favorite cells.

Marc Franssen

Marc Franssen

PhD Student
I focus mainly on lipid mediators in stroke and subarachnoid hemorrhage. In doing so I hope to explore how these lipid mediators modulate these pathologies. Specifically, the immunological response and that of the cells that make up the NVU is of great interest to me. For that purpose I am currently using LC-MS/MS, as well as trying to set a up a in vitro stroke model and hope to make use of 2-photon microscopy in the future.

Merel Rijnsburger

Merel Rijnsburger, PhD

Post-doctoral researcher
Studying the role of hormones in MS pathophysiology

Nienke de Wit

Nienke de Wit, PhD

Postdoctoral researcher
My research focuses on the blood-brain barrier in health and disease on a molecular level. Using in vitro cell systems and post-mortem human brain tissue I try to understand specific pathways that are necessary for maintaining proper barrier function.

Ruud Fontijn

Ruud Fontijn, PhD

Researcher
My work focuses on the blood-brain barrier, in particular on the endothelial component thereof. Mechanisms of blood-brain barrier failure in neurodegenerative diseases are assessed using in vitro models, impedance measurements, lentiviral genetic modification and various biochemical and molecular biological techniques.

Susanne van der Pol

Susanne van der Pol, Ing

Research Technician
Expertise in cell isolations, iPSC, cell-based assays, immunostainings (IHC, ICC, IF), CyTOF, FACS.

Wing Hee Fung

Wing Hee Fung, MD

PhD student
My research interests center around the neurovascular crosstalk in health and disease, especially in Multiple Sclerosis. In addition, my research focuses on immunomodulatory lipids to promote neurovascular health. High-throughput analysis is used to identify biomarkers for prediction of disease state, disease progression and therapeutic response in Multiple Sclerosis.

Other PI's

Sandra van Vliet

About

During her cum laude PhD and postdoctoral years Sandra J. van Vliet studied the impact of glycosylation and glycan-binding receptors on dendritic cell biology and specialized in the field of glyco-immunology. She obtained a prestigious NWO-VENI grant in 2010 that allowed her to dissect the signaling properties of glycan-binding receptors. With grants from the Dutch Cancer Society, Cancer Center Amsterdam and European Marie Curie ITN network she has established her own independent research group that aims to unravel how tumor glycans affect tumor progression, metastasis and anti-tumor immunity. In 2017, Sandra van Vliet was awarded the female career award ASPASIA from the Netherlands Organisation for Scientific Research (NWO). With the ASPASIA she established the VUmc Women in Science Fund, which aims to accelerate the careers of young female scientists by providing grants for international work visits and networking.

Research Line

How does aberrant tumor cell glycosylation affect tumor cell biology?

Cellular glycosylation is a highly dynamic process that alters upon activation, inflammation, and oncogenic transformation. Although it has been known for decades that cell surface glycans are highly diverse, it is still unclear how glycan heterogeneity is established and how this impacts tumor cell biology and tumor-immune cell recognition. We employ CRISPR/Cas9 genome engineering (both gene knockout as well as gene induction strategies) to generate isogenic tumor glycovariant cell lines. We assess the effect of tumor cell glycosylation on 3D tumor growth, as well as tumor cell differentiation, angiogenesis and drug resistance. Our new preliminary data (amongst others from RNAseq) points to an important role for cancer glycosylation in shaping tumor cell metabolism, epithelial-to-mesenchymal transition (EMT) and cancer stemness and this entails our future focus.

How does the tumor-associated glycome affect anti-tumor immunity?

Within the immune system, glycan blue prints are decoded by specific glycan-receptors, such as the C-type lectin (CLRs) or the Siglec receptors. These glycan-binding receptors are crucial in regulating the balance between immunity and tolerance and several CLRs and Siglecs seem to endow a tolerogenic phenotype on antigen presenting cells (APCs) to dampen potential immune responses directed against the tumor. We study this by correlating lectin binding to disease progression and immune cell infiltration and activation in human tumor samples.
To assess the immunological consequences of altered tumor glycosylation on a molecular level, we stimulate lectin receptors on dendritic cells and macrophages with synthetic glycoconjugates and glycan-modified dendrimers. These glycan-conditioned APC are subsequently profiled by RNAseq and characterized for their maturation marker expression, cytokine secretion and their ability to instruct effector and regulatory T cell responses. We are currently addressing whether targeting of lectin receptors also alters the metabolism of antigen presenting cells.

Figure: Staining of colorectal cancer tissue with a Fc-chimeric protein of the human C-type lectin MGL.

Key publications

  1. Cornelissen LAM, Blanas A, van der Horst JC, Kruijssen L, Zaal A, O’Toole T, Wiercx L, van Kooyk Y, van Vliet SJ. Disruption of sialic acid metabolism drives tumor growth by augmenting CD8(+) T cell apoptosis. Int J Cancer. 144(9):2290-2302 (2019)
  2. Marcelo F, Supekar N, Corzana F, van der Horst JC, Vuist IM, Live D, Boons GPH, Smith DF, van Vliet SJ. Identification of a secondary binding site in human macrophage galactose-type lectin by microarray studies: Implications for the molecular recognition of its ligands. J Biol Chem. 294(4):1300-1311 (2019).
  3. Blanas A, Cornelissen LAM, Kotsias M, van der Horst JC, van de Vrugt HJ, Kalay H, Spencer DIR, Kozak RP, van Vliet SJ. Transcriptional activation of fucosyltransferase (FUT) genes using the CRISPR-dCas9-VPR technology reveals potent N-glycome alterations in colorectal cancer cells. Glycobiology. 29(2):137-150 (2019)
  4. Blanas A, Sahasrabudhe NM, Rodríguez E, van Kooyk Y and van Vliet SJ. Fucosylated antigens in cancer: an alliance towards tumor progression, metastasis and resistance to chemotherapy. Front Oncol. 8:39 (2018)
    This article was selected for a special edition for World Cancer day 2019, highlighting a selection of top articles published in Frontiers in Oncology over the prior 12 months.
  5. Lenos K, Goos JACM, Vuist IM, den Uil SH, Delis-van Diemen PM, Belt EJTh, Stockmann HBAC, Bril H, de Wit M, Carvalho B, Giblett S, Pritchard CA, Meijer GA, van Kooyk Y, Fijneman RJA, van Vliet SJ. MGL ligand expression is correlated to BRAF mutation and associated with poor survival of stage III colon cancer patients Oncotarget 6(28):26278-90 (2015) ‒ IF 5.2, corresponding author

Group members

Irene Avila van der Haar

Irene van der Haar Àvila, MSc

PhDstudent
The focus of my PhD project is to evaluate the impact of sialylation on the anti-tumor response in colorectal cancer (CRC) by generating CRISPR/Cas9-based CRC cell lines with different levels of sialic acids. We aim to identify specific sialo-signatures that help in predicting response and success of cancer immunotherapy. For this, we make use of in vivo tumor models, multicolor (spectral) flow cytometry, microscopy imaging, IHC, co-culture assays, and RNA sequencing data.

Laraib Amir Ali

Laraib Amir Ali

Research technician
My project explores impact of tumor sialylation in tumor immunity. For this purpose we are generating sialo variant tumor cells lines of colorectal cancer (CRC) with distinct levels of sialic acid on their surface. We will also validate these results in metastatic tumor samples of CRC patients. Finally, we will employ long peptide vaccination strategies and immune checkpoint inhibition with anti PD-L1 to evaluate whether our different sialo variant tumors react differently to these immune stimulating treatment regimens.

Nadia van der Meijs

Nadia van der Meijs, MSc

PhD student
I’m investigating the signaling of the C-type lectin receptor MGL in dendritic cells in more detail by looking at, for example, the cytokine production, co-stimulatory and inhibitory receptor expression and gene expression patterns. With different MGL ligands, that induce a different conformation in MGL after binding, we hope to steer the immune response started by the dendritic cells in different directions.

Other PI's

Sergey Nejentsev

About

Sergey Nejentsev is professor of Translational Immunology and PI in the Department of Molecular Cell Biology and Immunology (MCBI) at Amsterdam UMC, location VUmc. After graduating as pediatrician in Russia, Sergey did his PhD with Prof Jorma Ilonen in Finland and then worked as a postdoc on genetics of type 1 diabetes in Prof John Todd’s lab in Cambridge. He then started his independent research group at the department of Medicine in the University of Cambridge investigating molecular mechanisms of immune-mediated disorders, including primary immunodeficiencies and susceptibility to infection. Sergey was awarded the Royal Society University Research Fellowship and the Wellcome Trust Senior Fellowship in Basic Biomedical Science. His research was also funded by the ERC Starting and ERC Advanced grants, MRC Programme grant as well as project grants from EU FP7 and Wellcome Trust. Sergey joined MCBI in October 2018.

Research Line

Primary Immunodeficiencies

Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders that affect functioning of the immune system and manifest with severe and/or recurrent infections. We identify causative mutations using whole exome or whole genome sequencing and then undertake detailed functional molecular analyses of the affected cellular pathways to uncover mechanisms leading to disease phenotypes. In this research, we closely collaborate with clinical scientists working with PID patients.

Our previous work includes the discovery of the Activated PI3K-Delta Syndrome (APDS), which is caused by a rare dominant gain-of-function mutation in phosphoinositide 3-kinase δ (Angulo et al, Science, 2013). APDS patients have antibody deficiency, suffer from recurrent respiratory infections and rapidly develop airway damage (bronchiectasis). Today, genetic analysis allows rapid diagnosis of APDS patients and they are being identified all around the world. Our findings also indicated that selective PI3Kδ inhibitors may provide a novel specific and efficient treatment for APDS, and this is now being tested in clinical trials. Furthermore, building on the findings in APDS patients we now investigate the role of human PI3Kδ in common diseases.

Our recent findings also include another novel PID, the complete RIPK1 deficiency. We showed that RIPK1-deficient immune cells have impaired proinflammatory signalling and are prone to cell death via the necroptosis pathway, which leads to dysregulated cytokine production, severe immune deficiency, arthritis and early-onset inflammatory bowel disease (Cuchet-Lourenco et al, Science, 2018). This finding highlighted the pivotal role of RIPK1 in the human immune system.

Host-pathogen interaction in tuberculosis

Tuberculosis (TB) is the leading cause of death among infectious diseases. People can be genetically predisposed to TB. Susceptibility to pulmonary TB is determined by combinations of multiple common DNA variants each having a small effect. To identify such variants, thousands of TB patients and healthy controls have to be studied. Previously, we have done a genome-wide association study in more than 11,000 subjects and identified a novel mechanism in TB mediated by the ASAP1 protein that controls dendritic cell migration (Curtis et al. Nat Genet 2015). Now we use CRISPR-Cas9 technology to further dissect mechanisms of interaction between human cells and Mycobacterium tuberculosis and develop novel host-directed therapies against TB. This research is funded by the ERC Advanced grant.

Human macrophages (red) and mycobacteria (green)
Actin meshwork (red) in human macrophages engulfing mycobacteria (yellow)

Key publications

  1. Cuchet-Lourenco D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J, Ceron-Gutierrez L, Bacon CM, Hackett S, Alsaleem B, Maes M, Gaspar M, Alisaac A, Goss E, Siegmund D, Wajant H, Kumararatne D, AlZahrani MS, Arkwright PD, Abinun M, Doffinger R and Nejentsev S: Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis and intestinal inflammation. Science 361:810-3, 2018
  2. Eletto D, Burns SO, Angulo I, Plagnol V, Gilmour KG, Henriquez F, Curtis J, Gaspar M, Nowak K, Daza-Cajigal V, Kumararatne D, Doffinger R, Thrasher AJ, Nejentsev S: Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nat Commun 7:13992, 2016
  3. Curtis J, Luo Y, Zenner HL, Cuchet-Lourenco D, Wu C, Lo K, Maes M, Alisaac A, Stebbings E, Liu JZ, Kopanitsa L, Ignatyeva O, Balabanova Y, Nikolayevskyy V, Baessmann I, Thye T, Meyer CG, Nurnberg P, Horstmann RD, Drobniewski F, Plagnol V, Barrett JC, Nejentsev S: Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet 47:523-527, 2015
  4. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers E, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S: Phosphoinositide 3-Kinase delta Gene Mutation Predisposes to Respiratory Infection and Airway Damage. Science 342:866-71, 2013
  5. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA: Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes. Science 324: 387-9, 2009
  6. Nejentsev S, Howson JMM, Walker NM, Szeszko JS, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, Hulme J, Maier LMM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Clayton DG, Todd JA and The Wellcome Trust Case Control Consortium: Localisation of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450: 887-92, 2007

Group members

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Elham Mirfazeli, MSc

PhD student
Activated phosphoinositide 3-kinase δ in systemic lupus erythematosus

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Eugénie Bassères, PhD

Research scientist
Host-pathogen interaction in tuberculosis

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Olivier Papapietro, PhD

Research scientist
Host-pathogen interaction in tuberculosis

Other PI's

Reina Mebius

About

Reina Mebius is professor in Molecular Cell Biology at the Department of Molecular Cell Biology & Immunology. She has contributed to the field of lymphoid organ development showing that communication between stromal cells and immune cells is crucial for the forming of lymph nodes. The realization that immune cell interaction with stromal cells is central to lymph node formation started another new research field in which the importance of stromal cells for the immune system is studied. Now the different roles that various stromal cell subsets have on the immune response during homeostasis and disease is further dissected using advanced techniques such as single cell RNA sequencing and fluorescence is situ hybridization, in order to discover novel points of interference for targeted therapy in autoimmunity and cancer.

Research Line

Functional development of the immune system

Lymphoid organs are built by a network of stromal cells, which are instrumental for formation of these organs in early ontogeny. Secondary lymphoid organs and their compartments greatly enhance the odds that rare antigen-specific T cells encounter dendritic cells that present the antigen and are thus crucial for effective immune responses. We study this process of lymph node formation and the cellular and molecular mechanisms that are required to form these highly organized lymphoid organs. Special attention is paid to the differentiation requirements of stromal precursor cells to the different stromal subsets that are present in adult lymphoid organs.

Figure, adapted from Koning et al, J. Immunology 2016, showing stromal cells in developing lymph nodes (left) in which the green and blue indicate stromal cells and red the immune cells and stromal cells in adult lymph nodes (right) in which different stromal cell subsets are indicted by red, blue and green.

Environmental control of the immune response

Stromal cells within the lymph nodes are able to convey location specific as well as survival signals to immune cells. The formation of lymphoid compartments is not restricted to ontogeny, since ectopic lymphoid structures are formed during chronic inflammatory diseases as well in solid tumours, where they can either contribute to the inflammatory response or an anti-tumour response, respectively. Within the organized structures various different stromal subsets are present, each with their own function. Further characterization of these functions reveal more specifics by which the immune system is controlled by its environment.

In addition, the micro environmental control outside of organized lymphoid organs are studied in inflammatory diseases as well as in cancer in order to better understand how the micro-environment contributes to disease.

Recent key publications

1. Gago da Graça C, van Baarsen LGM, Mebius RE. Tertiary Lymphoid Structures: Diversity in Their Development, Composition, and Role. J Immunol. 2021 Jan 15;206(2):273-281.
2. Nadafi R, Gago de Graça C, Keuning ED, Koning JJ, de Kivit S, Konijn T, Henri S, Borst J, Reijmers RM, van Baarsen LGM, Mebius RE.  Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses. Cell Rep. 2020 Mar 24;30(12):4110-4123.
3. Bar-Ephraim YE, Koning JJ, Burniol Ruiz E, Konijn T, Mourits VP, Lakeman KA, Boon L, Bögels M, van Maanen JP, Den Haan JMM, van Egmond M, Bouma G, Reijmers RM, Mebius RE. CD62L Is a Functional and Phenotypic Marker for Circulating Innate Lymphoid Cell Precursors. J Immunol. 2019 Jan 1;202(1):171-182.
4. Bar-Ephraim YE*, Cornelissen F*, Papazian N, Konijn T, Hoogenboezem RM, Sanders MA, Westerman BA, Gönültas M, Kwekkeboom J, Den Haan JMM, Reijmers RM, Mebius RE*, Cupedo T*. 2017. Cross-Tissue Transcriptomic Analysis of Human Secondary Lymphoid Organ-Residing ILC3s Reveals a Quiescent State in the Absence of Inflammation. Cell Rep. 21(3):823-833. * Equal contribution.
5. Koning JJ, Konijn T, Lakeman KA, O’Toole T, Kenswil KJ, Raaijmakers MH, Michurina TV, Enikolopov G, Mebius RE. 2016. Nestin-Expressing Precursors Give Rise to Both Endothelial as well as Nonendothelial Lymph Node Stromal Cells. J Immunol. 197:2686-94. 

Group members

Andrew Morrison

Andrew Morrison, MSC

PhD student
My project aims to develop a functional 3D organotypic lymph node with integrated lymphatics that mimic adaptive immune responses. Combining research on lymph node stromal cells and current in-house expertise of tissue engineering & microfluidic devices, the overall objective of the project is to design an organ-on-chip model that features lymphatic drainage of an immune competent gut into a lymph node. The immunosurveillance capability of the model will then be assessed by inducing an inflammatory response, leading to its availability as a future platform for rheumatoid arthritis drug testing.

profiel foto Eelco

Eelco Keuning, MSc

Lead technician
As lead technician my task is to organize and manage the laboratories at our department so everything runs smoothly. I do this together with our lab manager Ed Döpp. In this management position my role is to focus on quality and safety. In addition I’m the experimental animal research coordinator of the department, for which I function as central contact to all involved parties and can support in many different in vivo models, biotechnical techniques as well as several operations.

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Estefany Burniol Ruiz, MD

PhD student
In my research I focus on ILCs in IBD and the changing of homing markers. In 2019 my project became a part of the TIMID consortium. With TIMID we will be able to look at immune-cell alterations in PBMC’s in various immune-mediated diseases. Within the consortium we will be able to combine this with the data from all the other specialists in order to get better insights in these diseases.

Janna Roet

Janna Roet, MSc

PhD student
The focus of my project is to unravel the mechanisms of self-antigen expression in lymph node stromal cells, which is needed for the induction of peripheral tolerance. By using a whole-genome CRISPR activation screen we aim to identify the regulatory factors of self-antigen expression. Discovering these regulators will give more insights in fundamental mechanisms of autoimmunity and might be used to design new therapeutic strategies. For this project I make use of flow cytometry, multiplex microscopy, vector cloning and transfections, transductions and RNA sequencing data.

Lotte de Winde

Lotte de Winde, PhD

Research associate
I study the tumor-promoting role of lymph node stromal cells in B-cell lymphoma, and in sentinel lymph nodes draining from solid tumors (melanoma, breast cancer). More specifically, I investigate how interactions between lymph node stromal cells and tumor cells contribute to tumor progression by driving tumor cell dissemination and/or escaping anti-tumor immunity. In my projects, I use primary human lymph node and tumor material as well as cell lines in 2D and 3D co-culture assays, multicolor (spectral) flow cytometry, (advanced) fluorescence microscopy, and molecular and cell biology assays

Mariateresa Coppola

Mariateresa Coppola, MD, PhD

Postdoctoral researcher
Unrevealing new facets of the human immune responses fascinates me enormously, especially since I believe this knowledge can be translated into a better prevention and treatment of disabling immune-mediated diseases. Within the TargetToB consortium (Target to B – Target to B (target-to-b.nl)), I want to deep-phenotype B and follicular T-helper cells by mass-cytometry and further characterize newly-discovered cell populations with functional assays. This approach will increase our comprehension of the heterogeneous cell subsets involved in the pathogenesis of auto-immune diseases and cancer which is indispensable to identify novel biomarkers predicting therapy-outcomes and disease-prognosis.

Tanja_Konijn

Tanja Konijn, Ing

Research technician
I work together with Postdocs and AIO’s on several projects concerning lymph development and mucosal immunology. Since 2014 I became, in combination with my function as technician, an operator at the Microscopy & Cytometry Core Facility (MCCF).

Other PI's

Yvette van Kooyk

About

Yvette van Kooyk is professor in Molecular Cell Biology and Immunology,  head of the department Molecular Cell Biology and Immunology and PI of the Dendritic Cell Immunobiology group. Van Kooyk’s research team studies innate and adaptive immune responses guided by glycosylation. Her team unravels cellular communication driven by modified glycoproteins/lipids in cancer, allergy and autoimmunity. Central in her work is the development of new glycan modified  immune therapy for cancer and allergy, targeting glycan binding receptors on  skin resident antigens presenting cells that induce or inhibit immunity. Her other line of research is aimed to discover of glycan imposed regulatory immune imprinting by inflamed tissue and tumor microenvironment. She studies these questions in in-vivo mouse tumor models such as pancreatic cancer, lung and melanoma  in patient derived tissues and human in-vitro models such as skin model, tumor tissues and complex 3D culture models to identify  cellular communication at omics level in the context of tissue alterations.

She was awarded various NWO grants (PIONIER-ASPASIA), ERC Advanced-Eurostars and received the SPINOZA and van Loghem award for life time achievements in field of  (Glyco)-Immunology, and is a member of the Royal Netherlands Academy of Sciences (KNAW).

Research Line

Glyco-code in cancer and inflammatory diseases

We explore the innate immune system, with a focus on dendritic cells and macrophages, to develop novel therapeutics in cancer and inflammatory diseases.  Dendritic cells and macrophages have unique properties to act as  sensors for local changes and respond to tissue injury by producing inflammatory mediators or help  to eliminate injury and restore tissues. We study innate  glycan binding receptors that recognize glycosylated structures on pathogens or (altered) tissues, modulate immune activating or regulatory  programs of dendritic cells and myeloid cells. We investigate how binding of carbohydrates, altered due to tissue inflammation or wound healing processes, control modulation of immune cells  through recognition/signaling of glycan binding receptors, such as C-type lectins and Siglecs. We explore how glycan- glycan binding receptor control the immune signature and regulate tumor growth or pathogen recognition and inflammation.  Using transcriptomics and single cell sequencing we explore differential expression of glycosylation related genes in cancer patients tissues to unravel altered glycosylation signatures, to predict for survival benefit, response to therapy, and glycan induced immune modulation. We investigate how the glyco-code of the tumor-stromal network affects immune regulation. Using high dimensional cytometry and multiplex imaging we aim to define novel myeloid suppressive pathways in the tumor microenvironment of NSCLC, melanoma and PDAC. We also unravel how innate glycosylation in (tumor)tissue exert their effect on T cell and NK(T) cell function. New glycan immune regulatory programs will be studied in CRISPR-Cas9 generated glycan modified tumor/stromal mouse and human models, and glyco-code modifying therapies will be developed to revert suppression into tumor specific immunity. Next to cancer we study altered glycosylation processes in inflammatory diseases, such as rheumatoid arthritis, aimed to restore the immune balance towards suppression of the disease. 

TME of the Lung cancer using multiplex imaging. Tumor (white), immune markers (colors)

Glycan modified immune therapy for cancer and allergy

Professional antigen-presenting cells such as dendritic cells (DC) and Langerhans cells (LC) have also the capability to induce long-term cellular immunity.  We investigate  glycan binding receptors  such as C-type lectins and Siglecs on innate myeloid, macrophages and DC for targeting purposes to guide glycosylated antigens binding and uptake that influence antigen presentation, T cell differentiation and immune cell signaling. The cancer nano-vaccines we  develop use specific glycans that target receptors such as DC-SIGN and Langerin that  stimulate anti-tumor immunity, in human skin models and in-vivo mouse tumor models.  Using high dimensional flow analysis  local and systemic immune infiltrates and dynamics of the tumor microenvironment are studied. These DC targeting vaccines are combined with  immune checkpoints or other combinatorial therapies that alter immune regulatory processes in the tumor-microenvironment.  Immune inhibitory vaccines for treatment of auto-immune diseases and allergy use glycans that target glycans that interact with immune inhibitory receptors such as Siglecs.  We explore  T cell differentiation processes, antibody isotype responses, and the effect on innate immune cells, such as neutrophils and mast cells. Through fundamental discovery we aim to apply knowledge on glycan-DC modifying processes to be implemented in the treatment of cancer and inflammatory diseases.  

Glycan targeted vaccines (DC-SIGN/Langerin) for tumor immunity increasing T cell responses (red) or for reducing inflammatory responses, through Siglecs, aimed to induce tolerance (blue)

Key publications

  1. Glyco-Dendrimers as Intradermal Anti-Tumor Vaccine Targeting Multiple Skin DC Subsets. Duinkerken S, Horrevorts SK, Kalay H, Ambrosini M, Rutte L, de Gruijl TD, Garcia-Vallejo JJ, van Kooyk Y. Theranostics. 2019 Aug 12;9(20):5797-5809. doi: 10.7150/thno.35059
  2. The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol. 2018 Feb 5. doi: 10.1038/nri.2018.3.
  3. Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells.Perdicchio M, Ilarregui JM, Verstege MI, Cornelissen LA, Schetters ST, Engels S, Ambrosini M, Kalay H, Veninga H, den Haan JM, van Berkel LA, Samsom JN, Crocker PR, Sparwasser T, Berod L, Garcia-Vallejo JJ, van Kooyk Y, Unger WW.  Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):3329-34.
  4. Glycan modification of antigen alters its intracellular routing in dendritic cells, promoting priming of T cells.Streng-Ouwehand I, Ho NI, Litjens M, Kalay H, Boks MA, Cornelissen LA, Kaur Singh S, Saeland E, Garcia-Vallejo JJ, Ossendorp FA, Unger WW, van Kooyk Y. Elife. 2016 Mar 21;5. pii: e11765. doi: 10.7554/eLife.11765.
  5. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells Perdicchio M, Cornelissen LA, Streng-Ouwehand I, Engels S, Verstege MI, Boon L, Geerts D, Unger WW, van Kooyk Y. Oncotarget. 2016 Jan 5. doi: 10.18632/oncotarget.6822.

Group members

Aram de Haas

Aram de Haas, MSc

PhD Student
During my PhD within the DC4Balance consortium I am working on influencing the immune system by targeting specific C-type lectin receptors on antigen presenting cells with glycan-coated nanoparticles. The goal, depending on the formulation used, is to either induce an immune response against cancer, or dampen allergies. During my PhD I use various techniques such as multicolor (spectral) flow cytometry, moDC and T cell assays an in vivo models.

Brigitte-Carole Keumatio Doungtsop

Brigitte-Carole Keumatio Doungtsop

PhD Student
The focus of my research is the induction of antigen-specific tolerance to house dust mite allergens through the use of allergens from house dust mite conjugated to sialic acid to target Siglecs on antigen presenting cells. I assess the capacity of these antigen presenting cells to induce T regulatory cells and suppress the induction T helper 2 cells. I also assess the capacity of these allergen-sialic acid conjugates to suppress the production of IgE from B cells and to suppress the activity of mast cells and eosinophils.

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Chang Liu, MSc

PhD Student
The focus of my work is to search for some essential biomarkers in cancer-associated fibroblasts that could influence the metastasis of lung cancer. Furthermore, I want to reveal signalling pathways that those biomarkers relate to the metastasis and cell proliferation of NSCLC. For this project I make use of RNA sequencing data, CAM assay, IHC staining, Western Blotting and ELISA.

Eleonora Nardini

Eleonora Nardini, MSc

PhD student
My project aims at exploring sialylation of plasma derived /recombinant FVIII with as a strategy to induce preventive or therapeutic immune tolerance in hemophilia A (HA) patients. The development of anti – FVIII antibodies in ~ 20% of patients presents a major threat for the success of replacement therapies. Therefore, targeting Siglecs on dendritic cells with α2,3 sialic acid – FVIII is an attractive option to reduce FVIII immunogenicity and ameliorate the current treatment for HA.

Eveline-Li

Eveline Li, PhD

Postdoctoral Researcher/Project manager (DC4U)
Managment of sialic acid-related research towards the clinic

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Fabrizio Chiodo, PhD

Visiting Fellow
I study carbohydrate-mediated host-pathogens interactions. Knowing the molecular basis of these interactions and the immunological cascades linked to these events, are key elements to 1. Desing and understand carbohydrate-based vaccines; 2. Understand the innate system exploring carbohydrates as "potentiators"; 3. Explore the effects of microbiota in the context of the tumor microenvironment (lung cancer for example)

Joyce-Lübbers

Joyce Lübbers, PhD ING

Postdoctoral researcher
The focus of my work is targeting Siglecs on dendritic cells with sialic acids to induce antigen-specific tolerance as a therapeutic option for rheumatoid arthritis. Furthermore, I want to unravel the specific pathways that are changed upon sialic acid-receptor binding. For this project I make use of multicolor (spectral) flow cytometry, RNA sequencing data, metabolic assay, cytokine and binding ELISAs, and moDC and T cell assays.

Kelly Boelaars

Kelly Boelaars, MSc

PhD Student
I study stromal-immune cell interactions in the tumor microenvironment

Laura Kruijssen

Laura Kruijssen, MSc

Research technician
The focus of our research is finding immune therapies for cancer. On this moment the focus is on pancreatic cancer

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Prodhi Manisha, MSc

PhD student
My project focuses on the development of multimodal conjugate and nanotherapeutics consisting of (1) a sialidase to remove immunosuppressive sialic acids from the tumour microenvironment to incapacitate its ability for immune evasion, and (2) an antibody/nanobody to target the sialidase to tumour- and stroma-specific antigens. For my project, I will make use of flow cytometry, fluorescence-activated cell sorting, and various chemical techniques for the construction of conjugates and liposomes.

Sanne Duinkerken

Sanne Duinkerken, PhD

Postdoctoral researcher
Teaching immunology in different bachelor and master courses, while continuing in the tumor-immunology research with emphasis on vaccination strategies.

Other PI's

Jack van Horssen

About

Jack van Horssen is associated professor in at the Department of Molecular Cell Biology & Immunology and visiting professor at the Biomed Institute in Hasselt, Belgium Throughout his scientific career he has been interested in understanding the pathogenetic basis of neurodegenerative disorders. His research line focused on the identification of pathogenic processes and molecular pathways underlying multiple sclerosis (MS) disease progression with a main focus on understanding the pathological key events that are involved in inflammation-driven neurodegeneration. In the last years his interests in teaching and the development of innovative teaching strategies has grown and he is currently responsible for the bachelor programme Medicine. 

Key publications

  1. A. Kamermans, M. Rijnsburger, A. Chakraborty, S. van der Pol, H.E. de Vries*, J. van Horssen*. Reduced Angiopoietin-Like 4 Expression in Multiple Sclerosis Lesions Facilitates Lipid Uptake by Phagocytes via Modulation of Lipoprotein-Lipase Activity. *Authors contribute equally. Front Immunol. 2019 May 3;10:950.
  2. C.E. Leurs, P. Podlesniy, R. Trullas, L. Balk, M.D. Steenwijk, A. Malekzadeh, F. Piehl, B.M. Uitdehaag, J. Killestein, J. van Horssen*, C.E. Teunissen*. Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment. Mult. Scler. 2018 4:472-480
  3. .G. Nijland, R.J. Molenaar, S.M. van der Pol, P. van der Valk, C.J. van Noorden, H.E. de Vries, J. van Horssen. Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. Acta Neuropathol Commun. 2015, 1:79
  4. P.G. Nijland, M.E. Witte, B. van Het Hof, S. van der Pol, J. Bauer, H. Lassmann, P. van der Valk, H.E. de Vries, J. van Horssen. Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis.Acta Neuropathol. Commun. 2014 1:170
  5. M.E. Witte, P.G. Nijland, J.A. Drexhage, W. Gerritsen, D. Geerts, B. van het Hof, A. Reijerkerk, H.E. de Vries, P. van der Valk, J. van Horssen. Reduced expression of PGC-1alpha partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathol. 2013, 2:231-243

Group members

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Other PI's