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

Melanoma TRACERx Consortium, Renal TRACERx Consortium, Lung TRACERx Consortium, Babu Naidu

Research output: Contribution to journalArticlepeer-review

170 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)577-586
Number of pages10
JournalImmunity
Volume46
Issue number4
Early online date11 Apr 2017
DOIs
Publication statusPublished - 18 Apr 2017

Keywords

  • Animals
  • Antibodies, Monoclonal
  • Cell Line, Tumor
  • Flow Cytometry
  • Humans
  • Immunoglobulin Fc Fragments
  • Immunotherapy
  • Interleukin-2 Receptor alpha Subunit
  • K562 Cells
  • Kaplan-Meier Estimate
  • Lymphocyte Depletion
  • Mice
  • Neoplasms
  • Programmed Cell Death 1 Receptor
  • Protein Binding
  • Receptors, IgG
  • T-Lymphocytes, Regulatory
  • Journal Article

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