Cuende J.,Catholic University of Louvain |
Lienart S.,Catholic University of Louvain |
Dedobbeleer O.,Catholic University of Louvain |
Van Der Woning B.,ArGEN XBVBA |
And 14 more authors.
Science Translational Medicine | Year: 2015
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.