Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
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Date
2017-04-18ICR Author
Author
Arce Vargas, F
Furness, AJS
Solomon, I
Joshi, K
Mekkaoui, L
Lesko, MH
Miranda Rota, E
Dahan, R
Georgiou, A
Sledzinska, A
Ben Aissa, A
Franz, D
Werner Sunderland, M
Wong, YNS
Henry, JY
O'Brien, T
Nicol, D
Challacombe, B
Beers, SA
Melanoma TRACERx Consortium,
Renal TRACERx Consortium,
Lung TRACERx Consortium,
Turajlic, S
Gore, M
Larkin, J
Swanton, C
Chester, KA
Pule, M
Ravetch, JV
Marafioti, T
Peggs, KS
Quezada, SA
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Melanoma TRACERx Consortium
Renal TRACERx Consortium
Lung TRACERx Consortium
Cell Line, Tumor
K562 Cells
Animals
Humans
Mice
Neoplasms
Receptors, IgG
Antibodies, Monoclonal
Immunotherapy
Lymphocyte Depletion
Flow Cytometry
Protein Binding
Immunoglobulin Fc Fragments
T-Lymphocytes, Regulatory
Interleukin-2 Receptor alpha Subunit
Kaplan-Meier Estimate
Programmed Cell Death 1 Receptor
Research team
Melanoma and Kidney Cancer
Language
eng
Date accepted
2017-02-09
License start date
2017-04-11
Citation
Immunity, 2017, 46 (4), pp. 577 - 586
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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