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

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.

Metadata

Item Type:	Article
Authors/Creators:	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 Spain, L Wotherspoon, A Francis, N Smith, M Strauss, D Hayes, A Soultati, A Stares, M Spain, L Lynch, J Fotiadis, N Fernando, A Hazell, S Chandra, A Pickering, L Rudman, S Chowdhury, S Swanton, C Jamal-Hanjani, M Veeriah, S Shafi, S Czyzewska-Khan, J Johnson, D Laycock, J Bosshard-Carter, L Goh, G Rosenthal, R Gorman, P Murugaesu, N Hynds, RE Wilson, G Birkbak, NJ Watkins, TBK McGranahan, N Horswell, S Mitter, R Escudero, M Stewart, A Van Loo, P Rowan, A Xu, H Turajlic, S Hiley, C Abbosh, C Goldman, J Stone, RK Denner, T Matthews, N Elgar, G Ward, S Biggs, J Costa, M Begum, S Phillimore, B Chambers, T Nye, E Graca, S Al Bakir, M Hartley, JA Lowe, HL Herrero, J Lawrence, D Hayward, M Panagiotopoulos, N Kolvekar, S Falzon, M Borg, E
Copyright, Publisher and Additional Information:	© 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Dates:	Published: 18 April 2017 Published (online): 11 April 2017 Accepted: 9 February 2017
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	01 Jun 2017 15:29
Last Modified:	01 Jun 2017 15:29
Published Version:	http://doi.org/10.1016/j.immuni.2017.03.013
Status:	Published
Publisher:	Elsevier (Cell Press)
Refereed:	Yes
Identification Number:	10.1016/j.immuni.2017.03.013
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:117101

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

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