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. Fields of science medical and health sciencesclinical medicineoncologyprostate cancermedical and health sciencesclinical medicineoncologyskin cancermelanomanatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccinesmedical and health sciencesbasic medicineimmunologyimmunotherapy Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-CoG-2015 - ERC Consolidator Grant Call for proposal ERC-2015-CoG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution UNIVERSITE CATHOLIQUE DE LOUVAIN Net EU contribution € 1 993 125,00 Address PLACE DE L UNIVERSITE 1 1348 Louvain La Neuve Belgium See on map Region Région wallonne Prov. Brabant Wallon Arr. Nivelles Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 993 125,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITE CATHOLIQUE DE LOUVAIN Belgium Net EU contribution € 1 993 125,00 Address PLACE DE L UNIVERSITE 1 1348 Louvain La Neuve See on map Region Région wallonne Prov. Brabant Wallon Arr. Nivelles Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 993 125,00
