Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

Abstract

SummaryCD25 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.

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

“…First, anti-CD25 (clone PC61, rat (r)IgG1) or isotype control mAbs were administered 10 days prior to administration of SEB peptide together with anti-CTLA-4 mIgG2a or mIgG2a-N297A mAbs (Figure 3B). As reported previously, anti-CD25 mAb administration selectively reduced FoxP3 + Treg cells by approximately 50% throughout the assay (Figures 3B and S3A) (Arce Vargas et al, 2017). Despite Treg cell depletion, we observed a significant difference in the expansion of antigen-specific Vβ8 + effector T cells in anti-CTLA-4 mIgG2a mAb-injected mice, compared with the SEB peptide plus isotype mAb cohort (Figure 3C).…”

Comprehensive transcriptome profiling in elderly cancer patients reveals aging‐altered immune cells and immune checkpoints

“…Thus, when using checkpoint inhibitors in those cancers, the factor aging should be considered more carefully. According to our findings (upregulated Treg and innate immune cells), depletion of Treg via anti‐CD25 or promotion of innate immune cells through anti‐CD47 might be beneficial to current cancer immune therapy in elder patients . Because the enriched EMT and hypoxia in elder cancer patients, targeting these pathways such as blocking the function of TGFβ or HIF1α might also benefit current cancer immune therapy.…”

Targeting Treg cells in cancer immunotherapy

“…Therefore, it is critical to understand how tumor‐infiltrating Treg cells can be specifically depleted to enhance tumor immunity while tumor‐reactive effector T cells and peripheral Treg cells (i.e., lymphoid, tissue‐resident or circulating Treg cells) be preserved to prevent autoimmunity. Recent studies have addressed this issue and shown that differential control of tumor Treg versus effector T cells or peripheral Treg cells can be achieved by selecting specific target molecules (e.g., CTLA‐4) for antibody‐mediated depletion of tumor Treg cells by considering the differences in the kinetics and the level of such Treg‐targeting molecules expression by tumor Treg cells, effector T cells, and peripheral Treg cells, and by devising the ways of Treg cell depletion via systemic or local treatment with Treg‐depleting antibody , as discussed below.…”