Targeting GARP on human Tregs: a novel approach for the immunotherapy of cancer?
Transforming growth factor-b1 (TGF-b1) 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-b1 presented by GARP to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-b1 bound to an antibody that stabilizes the complex and blocks release of active TGF-b1. This reveals how GARP exploits an unusual medley of interactions, including fold complementation by the N-terminus of TGF-b1, to chaperone and orient the cytokine for binding and activation by αVβ8. Our work further elucidates the mechanism of antibody-mediated blockade of TGF-b1 activation and immunosuppression by Tregs. We also explored the therapeutic potential of blocking anti-GARP:TGF-b1 antibodies in murine models of cancer. 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.
- Liénart S., Merceron R., Vanderaa C., Lambert F., Colau D., Stockis J., van der Woning B., De Haard H., Saunders M., Coulie P.G., Savvides S.N., Lucas S. Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells.
Science. 362(6417):952-956, 2018
- Stockis J., Liénart S., Colau D., Collignon A., Nishimura S.L., Sheppard D.4, Coulie P.G., Lucas S. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8.
Proc Natl Acad Sci U S A. 114(47):E10161-E10168, 2017.
- Cuende J., Liénart S., Dedobbeleer O., van der Woning B., De Boeck G., Stockis1 J., Huygens C., Colau D., Somja J., Delvenne P., Hannon M., Baron F., Dumoutier L., Renauld J.-C., De Haard H., Saunders M., Coulie P.G. and Lucas S. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.
Science Translational Medicine. 7(284): 284ra56, 2015.
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