title: Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo.
abstract: 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.
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Julia
authors.initials: J
authors.lastname: Cuende
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Liénart
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dedobbeleer
authors.affiliation: arGEN-X BVBA, Technologiepark 30, B9052 Zwijnaarde, Gent, Belgium.
authors.forename: Bas
authors.initials: B
authors.lastname: van der Woning
authors.affiliation: arGEN-X BVBA, Technologiepark 30, B9052 Zwijnaarde, Gent, Belgium.
authors.forename: Gitte
authors.initials: G
authors.lastname: De Boeck
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Stockis
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Huygens
authors.affiliation: Ludwig Cancer Research, B1200 Brussels, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Colau
authors.affiliation: Department of Pathology, University Hospital of Liège, and Interdisciplinary Cluster of Applied Genoproteomics (GIGA), Laboratory of Experimental Pathology, University of Liège, B4000 Liège, Belgium.
authors.forename: Joan
authors.initials: J
authors.lastname: Somja
authors.affiliation: Department of Pathology, University Hospital of Liège, and Interdisciplinary Cluster of Applied Genoproteomics (GIGA), Laboratory of Experimental Pathology, University of Liège, B4000 Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Department of Pathology, University Hospital of Liège, and Interdisciplinary Cluster of Applied Genoproteomics (GIGA), Laboratory of Experimental Pathology, University of Liège, B4000 Liège, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Hannon
authors.affiliation: Department of Pathology, University Hospital of Liège, and Interdisciplinary Cluster of Applied Genoproteomics (GIGA), Laboratory of Experimental Pathology, University of Liège, B4000 Liège, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.affiliation: Ludwig Cancer Research, B1200 Brussels, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Dumoutier
authors.affiliation: Ludwig Cancer Research, B1200 Brussels, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: arGEN-X BVBA, Technologiepark 30, B9052 Zwijnaarde, Gent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: De Haard
authors.affiliation: arGEN-X BVBA, Technologiepark 30, B9052 Zwijnaarde, Gent, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium.
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.affiliation: de Duve Institute, Université catholique de Louvain, and WELBIO, B1200 Brussels, Belgium. sophie.lucas@uclouvain.be.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D015551:Autoimmunity; D000939:Epitopes / Q000737:chemistry; D006086:Graft vs Host Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011485:Protein Binding; D011487:Protein Conformation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007166:Immunosuppressive Agents; C087215:LRRC32 protein, human; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1