TARGETING TGF-Β ACTIVATION, LIKELY THE CORE MECHANISM OF IMMUNOSUPPRESSION BY HUMAN REGULATORY T CELLS
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 GARPmediated TGFβ1 production by human Tregs and perform structural analyses in the presence of these antibodies to identify tridimensional changes in GARP/TGFβ1 complexes that lead to the release of active TGFβ1.
- Identify and characterize additional proteins implicated in TGFβ1 activation by human Tregs, as GARP is required but not sufficient for TGFβ1 activation by Tregs.
- Determine the immunological and clinical impact of inhibitory antiGARP 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 antiGARP 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 nonTreg cells to better understand GARP functions, which remain largely unknown, and predict potential toxicities of antiGARP mAbs.
This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under the grant agreement number 682818.