Targeting GARP on human Tregs: a novel approach for the immunotherapy of cancer?
(2019) PIVAC-19 — Location: Athens, Greece (7.June.2019)
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- Abstract
- Transforming growth factor-β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, or cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This reveals how GARP exploits an unusual medley of interactions, including fold complementation by the N-terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Our work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by Tregs. Finally, we present analyses of GARP-expressing Tregs in human melanoma samples, which suggest that targeting GARP on human Tregs with blocking antibodies could represent an novel approach for the immunotherapy of cancer.
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Lucas, S. (2019). Targeting GARP on human Tregs: a novel approach for the immunotherapy of cancer? PIVAC-19, Athens, Greece. https://hdl.handle.net/2078.5/122725