Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo
Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo
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DOI：
10.1126/scitranslmed.aaa1983
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发表时间：
2015-04-22
影响因子：
17.1
通讯作者：
Lucas, Sophie
中科院分区：
文献类型：
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作者：
Cuende, Julia;Lienart, Stephanie;Lucas, Sophie
调节性T细胞（T-reg）对预防自身免疫至关重要，但过度的T-reg功能通过抑制抗肿瘤免疫应答而促进癌症进展。T-β 1通过产生活性转化生长因子-β 1（TGF-β 1）发挥免疫细胞的接触依赖性抑制作用。在T-reg细胞表面，TGF-β 1以非活性形式与膜蛋白GARP结合，然后通过未知机制激活。我们证明，GARP参与这种激活机制。产生了两种抗GARP单克隆抗体，其阻断人T-GFP产生活性TGF-β 1。这些抗体识别需要GARP/TGF-β 1复合物内的氨基酸GARP 137 -139的构象表位。识别其他GARP表位的各种抗体不阻断T-GFP的活性TGF-β 1产生。在NSG小鼠异种移植物抗宿主病模型中，阻断抗体抑制人T-IgM的免疫抑制活性。这些抗体可以作为治疗工具，通过与目前可用的免疫调节抗体不同的作用机制来增强对感染或癌症的免疫应答。单独使用或与肿瘤疫苗或靶向CTLA 4或PD 1/PD-L1通路的抗体联合使用，阻断抗GARP抗体可提高癌症免疫治疗的效率。
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.