Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors
&NA; 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 (Fc&ggr;R) 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 Fc&ggr;Rs 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. Graphical Abstract Figure. No caption available. HighlightsCD25 expression is largely restricted to Treg cells in mice and humansFc&ggr;RIIb inhibits anti‐CD25‐mediated depletion of intra‐tumoral Treg cellsFc‐optimized anti‐CD25 efficiently depletes intra‐tumoral Treg cellsAnti‐CD25 synergizes with PD‐1 blockade to reject established tumors &NA; 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 Fc&ggr;RIIb within tumors. Fc‐optimized anti‐CD25 mediates effective depletion of tumor‐infiltrating Treg cells and synergizes with PD‐1 blockade to promote tumor eradication.