Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
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DOI：
10.1016/j.immuni.2017.03.013
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发表时间：
2017-04-18
期刊：
影响因子：
32.4
通讯作者：
Quezada SA
中科院分区：
文献类型：
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作者：
Arce Vargas F;Furness AJS;Solomon I;Joshi K;Mekkaoui L;Lesko MH;Miranda Rota E;Dahan R;Georgiou A;Sledzinska A;Ben Aissa A;Franz D;Werner Sunderland M;Wong YNS;Henry JY;O'Brien T;Nicol D;Challacombe B;Beers SA;Melanoma TRACERx Consortium;Renal TRACERx Consortium;Lung TRACERx Consortium;Turajlic S;Gore M;Larkin J;Swanton C;Chester KA;Pule M;Ravetch JV;Marafioti T;Peggs KS;Quezada SA
CD 25在调节性T（Treg）细胞上以高水平表达，并且最初被提议作为癌症免疫疗法的靶点。然而，抗CD 25抗体对已建立的肿瘤显示出有限的活性。我们证明了CD 25表达在很大程度上限于小鼠和人类中的肿瘤浸润性Treg细胞。虽然观察到现有的抗CD 25抗体消耗外周中的Treg细胞，但肿瘤部位抑制性Fc γ受体（FcγR）IIb的上调阻止了肿瘤内Treg细胞消耗，这可能是先前在临床前模型中观察到的抗肿瘤活性缺乏的基础。使用与活化Fcγ R结合增强的抗CD 25抗体可有效清除肿瘤浸润性Treg细胞，提高效应细胞与Treg细胞的比率，并改善对已建立肿瘤的控制。与抗程序性细胞死亡蛋白-1抗体的组合促进了完全的肿瘤排斥，证明了CD 25作为治疗靶点的相关性，以及在免疫肿瘤学中用于未来组合方法的有前景的底物。在小鼠和人中，CD 25表达主要限于Treg细胞FcγRIIb抑制抗CD 25介导的肿瘤内Treg细胞耗竭Fc优化的抗CD 25有效耗竭肿瘤内Treg细胞抗CD 25与PD-1阻断协同作用以排斥已建立的肿瘤抗CD 25抗体对已建立的肿瘤仅显示出适度的治疗活性。Arce Vargas等人证明现有的抗CD 25抗体由于肿瘤内FcγRIIb的上调而不能耗尽肿瘤内Treg细胞。Fc优化的抗CD 25介导肿瘤浸润性Treg细胞的有效消耗，并与PD-1阻断协同作用以促进肿瘤根除。
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology. CD25 expression is largely restricted to Treg cells in mice and humans FcγRIIb inhibits anti-CD25-mediated depletion of intra-tumoral Treg cells Fc-optimized anti-CD25 efficiently depletes intra-tumoral Treg cells Anti-CD25 synergizes with PD-1 blockade to reject established tumors Anti-CD25 antibodies have displayed only modest therapeutic activity against established tumors. Arce Vargas et al. demonstrate that existing anti-CD25 antibodies fail to deplete intra-tumoral Treg cells due to upregulation of FcγRIIb within tumors. Fc-optimized anti-CD25 mediates effective depletion of tumor-infiltrating Treg cells and synergizes with PD-1 blockade to promote tumor eradication.