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Discriminating signalling nodes in conventional and regulatory T cells to guide clinical targeting of costimulatory receptors in cancer, autoimmunity and transplant rejection.

Projectomschrijving

T-cellen kunnen geinfecteerde lichaamscellen en kankercellen doodmaken. Onschuldige cellen moeten ze met rust laten. Om actief te worden hebben T-cellen toestemming nodig van ‘receptoren’op hun oppervlak. Die receptoren gebruiken signaleringsmoleculen in de cel om deze te activeren. Naast ‘gewone’ T cellen, bestaan er ook ‘regulatoire’ T-cellen. Deze cellen remmen de gewone T-cellen af om te voorkomen dat die onschuldige lichaamscellen aanvallen. Op regulatoire en gewone T-cellen zitten dezelfde receptoren. In dit projekt onderzoeken we of de twee typen T cellen verschillende signaleringsmoleculen gebruiken. Als we verschillen vinden, kunnen we geneesmiddelen ontwikkelen, die de relevante signaleringsmoleculen blokkeren. Hiermee kunnen we dan specifiek de regulatoire T cellen uitschakelen om sterkere afstoting van kankercellen door gewone T-cellen te krijgen. Andere medicijnen kunnen dan specifiek gewone T cellen afremmen, bv om afstoting van orgaantransplantaten te voorkomen.

Producten

Titel: Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses
Auteur: Nadafi, Reza, Gago de Graça, Catarina, Keuning, Eelco D., Koning, Jasper J., de Kivit, Sander, Konijn, Tanja, Henri, Sandrine, Borst, Jannie, Reijmers, Rogier M., van Baarsen, Lisa G.M., Mebius, Reina E.
Magazine: Cell Reports
Titel: GPA33: A Marker to Identify Stable Human Regulatory T Cells
Auteur: Opstelten, Rianne, de Kivit, Sander, Slot, Manon C., van den Biggelaar, Maartje, Iwaszkiewicz-Grzes, Dorota, Gliwinski, Mateusz, Scott, Andrew M., Blom, Bianca, Trzonkowski, Piotr, Borst, Jannie, Cuadrado, Eloy, Amsen, Derk
Magazine: Journal of Immunology
Titel: Proteomic Analyses of Human Regulatory T Cells Reveal Adaptations in Signaling Pathways that Protect Cellular Identity
Auteur: Cuadrado, Eloy, van den Biggelaar, Maartje, de Kivit, Sander, Chen, Yi-yen, Slot, Manon, Doubal, Ihsane, Meijer, Alexander, van Lier, Rene A.W., Borst, Jannie, Amsen, Derk
Magazine: Immunity

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Samenvatting van de aanvraag

Background: In the past three decades, many receptors that control the activity of immune cells have been identified. As a result, various immune cell receptors are now clinical targets in cancer and autoimmune disease. In particular, T-cell costimulatory and coinhibitory receptors are at center stage in antibody-based drug development. The recent successes of such antibodies in cancer immunotherapy highlight this process, with complete responses and cures in metastatic melanoma patients that were non-responsive to any other therapy. The challenge is now to ensure that such immunomodulatory drugs will bring clinical benefit, with high success rate and no, or acceptable side effects. The problem: Immune responses depend on a dynamic balance between the opposing activities of two types of T cells: conventional T cells (Tconv) and regulatory T cells (Treg). Treg restrain the activity of conventional CD4 and CD8 T-cells and thereby prevent autoimmunity. Treg are thus beneficial, but they also constrain anti-tumor immune responses and responses to chronic infections. For this reason, we want to promote or inhibit Treg functions at wish for therapeutic purposes. The problem is that Tconv and Treg express the same costimulatory and coinhibitory receptors. Therefore, receptor-targeted approaches that were developed based on their modulation of Tconv may be less effective due to activity on Treg or vice versa. Current knowledge is too limited to allow for rational prediction of the therapeutic effect. Towards the answer: There are clear indications that in Treg, signalling pathways for cell survival, metabolism and proliferation operate differently from those in Tconv. Certain differences have already been noted for key receptors that drive the T-cell response. This provides an opportunity for selective manipulation of Tconv or Treg. For this reason, we need to understand more about signal transduction differences in Tconv and Treg. Aim: This proposal aims to identify differences in signaling nodes for cell survival, metabolism and proliferation in Tconv and Treg, with a focus on signaling by costimulatory TNF receptor family members. We will determine and validate the key differential signalling events and select for drugs that differently affect these opposing cell types. Outlook: Our work will identify certain signalling nodes that may be used as drug targets to steer the T-cell response in the desired direction. The outcome of this project will result in a deeper understanding in the delicate balance between Tcon and Treg. This knowledge will spur novel drug development that will benefit patients in need of immune activation (cancer, infection), as well as patients in need of immunne suppression (autoimmunity or transplant rejection). Our position in the field: The applicants have discovered the T-cell costimulatory CD27/CD70 receptor/ligand system and have been internationally leading in the delineation of its mode of action. The collective studies inarguably identify the CD27/CD70 system as a promising clinical target in cancer and autoimmune diseases. Our collaboration with Dutch biotech industry has yielded a unique, patented CD27-agonist antibody that is under development as a clinical agent in cancer immunotherapy. The knowledge and tools obtained in this project will permit targeting of CD27/CD70 and related costimulatory systems in specific indications and in the correct combination with cooperating chemical drugs. This project aims to develop the critical insights that will guide clinical application of CD27/CD70 targeted agents. The CD27/CD70 costimulatory system is part of a large TNF receptor/ligand family harbouring many clinical targets. The research proposed here will therefore serve as a lead in the rational combined antibody/drug targeting of other costimulatory systems in this family.

Onderwerpen

Kenmerken

Projectnummer:
91213071
Looptijd: 100%
Looptijd: 100 %
2014
2019
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. R.A.W. van Lier
Verantwoordelijke organisatie:
Sanquin Blood Supply Foundation