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

被引:126
作者
Cuende, Julia [1 ,2 ]
Lienart, Stephanie [1 ,2 ]
Dedobbeleer, Olivier [1 ,2 ]
van der Woning, Bas [3 ]
De Boeck, Gitte [3 ]
Stockis, Julie [1 ,2 ]
Huygens, Caroline [1 ,2 ]
Colau, Didier [4 ]
Somja, Joan [5 ,6 ]
Delvenne, Philippe [5 ,6 ]
Hannon, Muriel [5 ,6 ]
Baron, Frederic [5 ,6 ]
Dumoutier, Laure [4 ]
Renauld, Jean-Christophe [4 ]
De Haard, Hans [3 ]
Saunders, Michael [3 ]
Coulie, Pierre G. [1 ,2 ]
Lucas, Sophie [1 ,2 ]
机构
[1] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium
[2] WELBIO, B-1200 Brussels, Belgium
[3] arGEN X BVBA, B-9052 Ghent, Belgium
[4] Ludwig Canc Res, B-1200 Brussels, Belgium
[5] Univ Liege, Univ Hosp Liege, Dept Pathol, B-4000 Liege, Belgium
[6] Univ Liege, Lab Expt Pathol, Interdisciplinary Cluster Appl Genoprote GIGA, B-4000 Liege, Belgium
关键词
GROWTH-FACTOR-BETA; LATENT TGF-BETA; IMMUNE-SYSTEM; HUMAN TREG; HUMAN-IGG; EXPRESSION; FOXP3; MELANOMA; SURFACE; MICE;
D O I
10.1126/scitranslmed.aaa1983
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Regulatory T cells (T-regs) are essential to prevent autoimmunity, but excessive T-reg function contributes to cancer progression by inhibiting antitumor immune responses. T-regs exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-beta 1 (TGF-beta 1). On the T-reg cell surface, TGF-beta 1 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-beta 1 by human T-regs. These antibodies recognize a conformational epitope that requires amino acids GARP137-139 within GARP/TGF-beta 1 complexes. A variety of antibodies recognizing other GARP epitopes did not block active TGF-beta 1 production by T-regs. In a model of xenogeneic graft-versus-host disease in NSG mice, the blocking antibodies inhibited the immunosuppressive activity of human T-regs. 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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页数:12
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