Sophie Lucas

Major achievements

• Monoclonal antibodies to block TGF-β1 production and immunosuppression by GARP+ Tregs to treat patients with cancer (in clinical trials since 2019)
• ERC Consolidator Grant (2016-2021)
• Partnerships with industry (argenx since 2015; AbbVie since 2019)

Question

What mechanisms enable immunosuppressive cells to produce TGF-β, and can we target them with new drugs to treat cancer or other immune-related diseases ?

Research focus

3D structure of TGF-β1 presented by GARP on Tregs, bound and blocked by an anti-GARP antibody which could serve currently tested in the clinics for the immunotherapy of cancer.

Our research focuses on understanding the molecular mechanisms by which cells known as Tregs suppress immune responses, with the long-term objective to develop new drugs to treat patients with cancer or auto-immune diseases. We found out previously that production of TGF-β1 is one important mechanism by which Tregs suppress anti-tumor immunity in cancer patients. TGF-β1, β2, and β3 molecules are closely related members of the Transforming Growth Factor beta (TGF-β) superfamily of growth factors. They are encoded by distinct genes and exert major roles during organ development in utero, and in wound healing and immune responses in adults. Owing to their potency and variety of effects, the three TGF-βs are produced as latent, inactive precursors that require activation to exert biological activity. The mechanisms of TGF-β activation appear to be isoform- and cell type-specific. We discovered a mechanism of TGF-β1 activation that operates on the surface of human Tregs and implies transmembrane proteins GARP and αVβ8. We developed antibodies binding GARP:TGF-β1 complexes that block TGF-β1 activation and immunosuppression by Tregs. One of our antibodies is currently tested in clinical trials for cancer immunotherapy.

At variance with our laboratory’s previous major interests in oncology, we are now also exploring the role of GARP-dependent and -independent activation of TGF-β isoforms in auto- and allo-immune responses, with the goal of developing new therapeutic approaches for patients suffering from auto-immunity or graft-versus-host disease.