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

Periodic Reporting for period 4 - TARG-SUP (Targeting TGF-β activation, likely the core mechanism of immunosuppression by human regulatory T cells.)

Período documentado: 2020-10-01 hasta 2021-03-31

Novel approaches for the treatment of cancer, collectively termed “cancer immunotherapies”, started to reach the clinic in 2011 and are yielding spectacular results, unfortunately only in a limited proportion of patients. Immunotherapeutic reagents aim at stimulating the immune system of cancer patients, to induce destruction of tumor cells by immune effector cells such as anti-tumor T lymphocytes. Monoclonal antibodies that target inhibitory receptors CTLA-4 or PD1 on the surface of T lymphocytes were approved by the FDA and many European countries for the treatment of several types of cancers, including metastatic melanoma and lung adenocarcinomas. Some of these monoclonal antibodies provided impressive clinical benefits to patients, with up to 30-40% patients experiencing tumor regressions, including complete and very long-term rejections. However, a majority of cancer patients still do not respond to available immunotherapies, owing to the existence of potent immunosuppressive mechanisms that paralyse the activity of anti-tumor T lymphocytes within tumor lesions. Our project explores the hypothesis that regulatory T cells (aka Tregs) may exert important immunosuppressive activity on anti-tumor T cells. Our global objective is to generate therapeutic reagents that tamper with the mechanisms by which Tregs suppress other T cells. These reagents could serve as a novel form of immunotherapy, which could be used alone or in combination with existing forms of cancer treatments. Our hope is to develop a novel approach of cancer immunotherapy that is more efficient and less toxic than the currently available treatments. While developing these tools, we also aim at better understanding the fundamental biology which underlies the immunosuppressive functions of Tregs, cells which also play important roles in non-cancerous human diseases such as autoimmunity and chronic infections.
Shortly before the start of this project, we had identified an immunosuppressive mechanism that operates on the surface of human Tregs. This mechanism involves a protein called GARP. GARP binds an inactive form of a very potent immunosuppressive molecule known as TGF-ß1, and presents it on the surface of Tregs. Once activated, TGF-ß1 exerts short distance immunosuppression by conveying an inhibitory message to neighbouring cells such as anti-tumor T lymphocytes. We obtained monoclonal antibodies against GARP that block the release of active TGF-ß1 from human Tregs. We could demonstrate that the blocking anti-GARP antibodies bind simultaneously to GARP and to two different parts of the inactive TGF-ß1 presented on Tregs. We used X-ray crystallography, a method that has been used to study the structure of molecules for a bit more than a century and that is still being developed for the study of biological macromolecules at atomic resolution. We discovered that GARP resembles a horseshoe that is straddled by TGF-ß1. The two molecules are so intricately assembled that TGF-ß1 itself contributes to the structure of the GARP horseshoe. The antibody fragment sticks to both GARP and TGF-ß1 in the assembly. It appears to glue the two molecules to one another, ensuring that when other molecules pull on one part of the assembly, the small, active part of TGF-ß1 is not released, and is thus prevented from conveying its inhibitory message. These results provide very solid mechanistic explanations for the ability of our anti-GARP antibodies to block the immunosuppressive function of Tregs. They were published in the journal “Science” in November 2018. We also discovered that GARP is helped in its function to activate TGF-ß1 on the surface of Tregs by a protein called integrin alphaVbeta8. Antibodies against alphaVbeta8 also block active TGF-ß1 release and immunosuppression by human Tregs. We published these results in the journal “PNAS” in 2017. Finally, we also observed that GARP is not only expressed on Tregs, but also on other types of immune cells including B lymphocytes. GARP also promotes release of active TGF-ß1 by B cells, allowing them to produce a specific type of antibody called IgAs, which are very important to protect our organism against microbes at the level of our epithelia. These results were published in the “Journal of Immunology”.
Altogether, we could identify the mechanism of action of anti-GARP antibodies that block immunusuppression by Tregs. These discoveries sparked the interest of the pharmaceutical company AbbVie, who announced in August 2018 the exercise of its exclusive license option to develop and commercialize our anti-GARP antibody ARGX-115. We are continuing our analyses of the anti-tumor effects of anti-GARP antibodies in pre-clinical models, and are pursuing our attempts to identify the functions of GARP on Tregs and non-Treg cells in the context of cancer, autoimmunity and chronic infections.
Crystal structure of GARP/TGF-beta complexes blocked by an anti-GARP antibody