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 (FcgammaR) 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 FcgammaRs 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.
Author Info: (1) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (2) Canc
Author Info: (1) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (2) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK; The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (3) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (4) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK; The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (5) Research Department of Oncology, UCL Cancer Institute, London WC1E 6DD, UK. (6) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (7) Research Department of Oncology, UCL Cancer Institute, London WC1E 6DD, UK. (8) Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. (9) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (10) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (11) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (12) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (13) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (14) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (15) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (16) Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK. (17) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (18) Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK. (19) Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Southampton SO17 1BJ, UK. (20) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; The Francis Crick Institute, London NW1 1AT, UK. (21) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (22) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (23) The Francis Crick Institute, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London WC1E 6DD, UK. (24) Research Department of Oncology, UCL Cancer Institute, London WC1E 6DD, UK. (25) Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (26) Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA. (27) Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (28) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: k.peggs@ucl.ac.uk. (29) Cancer Immunology Unit, University College London Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk.
