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Sci Transl Med. 2015 Apr 22;7(284):284ra56. doi: 10.1126/scitranslmed.aaa1983.

Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.

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de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
arGEN-X BVBA, Technologiepark 30, B9052 Zwijnaarde, Gent, Belgium.
Ludwig Cancer Research, B1200 Brussels, Belgium.
Department of Pathology, University Hospital of Liège, and Interdisciplinary Cluster of Applied Genoproteomics (GIGA), Laboratory of Experimental Pathology, University of Liège, B4000 Liège, Belgium.
de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.


Regulatory T cells (Tregs) are essential to prevent autoimmunity, but excessive Treg function contributes to cancer progression by inhibiting antitumor immune responses. Tregs exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-β1 (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. Two anti-GARP monoclonal antibodies were generated 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 Tregs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human Tregs. These 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 tumor vaccines or antibodies targeting the CTLA4 or PD1/PD-L1 pathways, blocking anti-GARP antibodies may improve the efficiency of cancer immunotherapy.

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