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TARG-SUP SIGNED

Targeting TGF-β activation, likely the core mechanism of immunosuppression by human regulatory T cells.

Total Cost €

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EC-Contrib. €

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Partnership

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Project "TARG-SUP" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITE CATHOLIQUE DE LOUVAIN 

Organization address
address: PLACE DE L UNIVERSITE 1
city: LOUVAIN LA NEUVE
postcode: 1348
website: www.uclouvain.be

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Belgium [BE]
 Total cost 1˙993˙125 €
 EC max contribution 1˙993˙125 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-CoG
 Funding Scheme ERC-COG
 Starting year 2016
 Duration (year-month-day) from 2016-04-01   to  2021-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITE CATHOLIQUE DE LOUVAIN BE (LOUVAIN LA NEUVE) coordinator 1˙993˙125.00

Map

 Project objective

Regulatory T lymphocytes (Tregs) inhibit immune responses and are required to maintain immune tolerance. Tregs express membrane protein GARP, which displays latent TGF-β1 on the cell surface. Immunosuppression by human Tregs appears to require GARP-mediated activation of TGF-β1. My objectives are to unravel the molecular aspects of TGF-β1 activation by GARP and determine the functional importance of this process in physiological and pathological conditions where Tregs or other GARP-expressing cells are present. As this implies the development of new tools to modulate GARP-dependent TGF-β1 activation and Treg immunosuppression, we will also explore their potential for the treatment of immune-related human diseases, and notably cancer. More specifically, I will: - Derive antibodies that modulate GARP-mediated TGF-β1 production by human Tregs and perform structural analyses in the presence of these antibodies to identify tri-dimensional changes in GARP/TGF-β1 complexes that lead to the release of active TGF-β1. - Identify and characterize additional proteins implicated in TGF-β1 activation by human Tregs, as GARP is required but not sufficient for TGF-β1 activation by Tregs. - Determine the immunological and clinical impact of inhibitory anti-GARP mAbs on cancer in mice. We will derive anti-murine GARP mAbs. As an alternative, we will generate mutant mice expressing a chimeric mouse/human GARP that is recognized by anti-human GARP mAbs. The antibodies will be tested in tumour-bearing mice treated or not with other immunotherapies including vaccines or immunostimulatory antibodies. - Determine whether blocking anti-GARP mAbs improve immune responses to microbial vaccines or to chronic infections, as these represent important applications for transient inhibition of Treg activity in humans. - Analyse the expression and roles of GARP in non-Treg cells to better understand GARP functions, which remain largely unknown, and predict potential toxicities of anti-GARP mAbs.

 Publications

year authors and title journal last update
List of publications.
2018 Stéphanie Liénart, Romain Merceron, Christophe Vanderaa, Fanny Lambert, Didier Colau, Julie Stockis, Bas van der Woning, Hans De Haard, Michael Saunders, Pierre G. Coulie, Savvas N. Savvides, Sophie Lucas
Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells
published pages: 952-956, ISSN: 0036-8075, DOI: 10.1126/science.aau2909
Science 362/6417 2019-04-18

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