Sophie Lucas - Targeting GARP on Tregs: a novel approach for cancer immunotherapy ?

Regulatory T lymphocytes (Tregs) are essential to prevent auto-immunity, but excessive Treg function contributes to cancer progression by inhibiting anti-tumor immune responses. Tregs exert contact-dependent inhibition of immune cells through the production of active TGF-β1. On the Treg cell surface, TGF-β1 is in an inactive form bound to membrane protein GARP and then activated by an unknown mechanism. We demonstrate that GARP is involved in this activation mechanism. We generated anti-human GARP monoclonal antibodies that block the production of active TGF-β1 by human Tregs. These antibodies recognize a conformational epitope that requires amino-acids GARP137-139 within GARP/TGF-β1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-β1 production by human Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, blocking antibodies inhibited the immunosuppressive activity of human Tregs. We also derived anti-murine GARP antibodies that block active TGF-β1 production by mouse Tregs. These antibodies inhibit the growth of P815 mastocytoma in DBA/2 mice when used as monotherapies. Altogether, our data show that anti-GARP antibodies may serve as therapeutic tools to boost immune responses to infection or cancer, via a mechanism of action distinct from that of currently available immunomodulatory antibodies. Used alone or in combination with other therapeutic reagents, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy.

Prof. Sophie Lucas - Duve Institute, Université catholique de Louvain (UCL), Brussels, Belgium

I acquired an M.D. degree in 1994 and a Ph.D. degree in 2000 for my work in the field of tumour immunology under the mentorship of Prof. Thierry Boon. I identified and characterised novel genes encoding human tumour-specific antigens, some of which were used in clinical trials of therapeutic vaccination against cancer. My early post-doctoral work was devoted to studying new cytokines and cytokine receptors in the laboratory of F. de Sauvage at Genentech, a bio-technological company located in San Francisco (USA). In 2004, I founded my own research group at the de Duve Institute (Faculty of Medicine, UCL, Brussels). The long-term objective of my research is to identify molecular mechanisms by which regulatory T cells (Tregs) inhibit anti-tumour T cell responses, with the hope to develop targeted strategies to improve the efficacy of cancer immunotherapy. My work is now focused on identifying the molecular mechanisms by which regulatory T cells inhibit anti-tumour immune responses in cancer patients, with a particular emphasis on the production of active TGF-β, a cytokine with potent immune suppressive functions.