Journal
IMMUNITY
Volume 46, Issue 4, Pages 577-586Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2017.03.013
Keywords
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Funding
- Cancer Research Institute
- CRUK [C36463/A20764, C11496/A17786]
- NIHR BTRU for Stem Cells and Immunotherapies [167097]
- CRUK-UCL Centre [C416/A18088]
- CRUK's Lung Cancer Centre of Excellence [C5759/A20465]
- CRUK
- Engineering and Physical Sciences Research Council at King's College London and UCL [C1519/A16463]
- Cancer Immunotherapy Accelerator Award (CITA-CRUK) [C33499/A20265]
- Sam Keen Foundation/RMH NIHR Biomedical Research Centre, Bloodwise [08022/P4664]
- Department of Health
- Cancer Research UK [20537, 20465, 23464, 15951, 12100, 19740, 15953, 22795, 22246, 19278, 18176, 17891, 20275, 15954, 20764, 20276, 16463] Funding Source: researchfish
- Medical Research Council [MR/P024351/1] Funding Source: researchfish
- National Institute for Health Research [CL-2015-17-002] Funding Source: researchfish
- Pancreatic Cancer UK [2013 RIF - Shaw] Funding Source: researchfish
- The Francis Crick Institute [C50947/A18176, 10002] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [20265, 20613, 18892] Funding Source: researchfish
- MRC [MR/P024351/1] Funding Source: UKRI
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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 gamma 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 gamma 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.
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