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Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors

Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors
Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors

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.

Journal Article
1097-4180
577-586
Arce Vargas, Frederick
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Furness, Andrew J.S.
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Solomon, Isabelle
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Joshi, Kroopa
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Mekkaoui, Leila
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Lesko, Marta H.
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Miranda Rota, Enrique
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Dahan, Rony
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Georgiou, Andrew
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Sledzinska, Anna
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Ben Aissa, Assma
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Franz, Dafne
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Werner Sunderland, Mariana
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Wong, Yien Ning Sophia
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Henry, Jake Y.
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O'Brien, Tim
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Nicol, David
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Challacombe, Ben
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Beers, Stephen A.
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Turajlic, Samra
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Gore, Martin
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Larkin, James
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Swanton, Charles
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Chester, Kerry A
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Pule, Martin
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Ravetch, Jeffrey V.
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Marafioti, Teresa
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Peggs, Karl S.
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Quezada, Sergio A.
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[error in script]
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Arce Vargas, Frederick
893cc199-2be3-4fb7-8cfc-56c53ec784df
Furness, Andrew J.S.
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Solomon, Isabelle
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Joshi, Kroopa
48c0bcbb-88f7-405d-b5f3-4126ab80b67a
Mekkaoui, Leila
e6c623d9-791e-4ffe-a268-20b254a9f99a
Lesko, Marta H.
7fdb3a8a-f1b2-4c2a-9973-d855a8178f06
Miranda Rota, Enrique
b75d8115-1666-4b5c-994a-da70fc7c84fd
Dahan, Rony
ade40cab-36c3-4be0-908d-382af763e2d5
Georgiou, Andrew
72c5cebc-3ed4-4f5f-9e42-03a60fdcb6b1
Sledzinska, Anna
496be81a-5d6e-4a66-9ce4-a80fbd0df0f8
Ben Aissa, Assma
ee2800f2-9821-46af-9866-539d26b2bc7c
Franz, Dafne
14313fc7-f515-49e7-a82c-f6f1f5932a3a
Werner Sunderland, Mariana
444271cb-2a8d-435d-b409-d9f2ce6040b9
Wong, Yien Ning Sophia
b910e442-5fca-44c0-bea5-cac64645e8ee
Henry, Jake Y.
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O'Brien, Tim
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Nicol, David
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Challacombe, Ben
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Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Turajlic, Samra
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Gore, Martin
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Larkin, James
00cc13b2-a896-4745-9664-732b26ec38ee
Swanton, Charles
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Chester, Kerry A
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Pule, Martin
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Ravetch, Jeffrey V.
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Marafioti, Teresa
2036b6e2-1157-4170-a533-a7c2307d619b
Peggs, Karl S.
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Quezada, Sergio A.
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Arce Vargas, Frederick, Furness, Andrew J.S., Solomon, Isabelle, Joshi, Kroopa, Mekkaoui, Leila, Lesko, Marta H., Miranda Rota, Enrique, Dahan, Rony, Georgiou, Andrew, Sledzinska, Anna, Ben Aissa, Assma, Franz, Dafne, Werner Sunderland, Mariana, Wong, Yien Ning Sophia, Henry, Jake Y., O'Brien, Tim, Nicol, David, Challacombe, Ben, Beers, Stephen A., Turajlic, Samra, Gore, Martin, Larkin, James, Swanton, Charles, Chester, Kerry A, Pule, Martin, Ravetch, Jeffrey V., Marafioti, Teresa, Peggs, Karl S. and Quezada, Sergio A. Melanoma TRACERx Consortium, Renal TRACERx Consortium and Lung TRACERx Consortium (2017) Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors Immunity, 46, (4), pp. 577-586. (doi:10.1016/j.immuni.2017.03.013).

Record type: Article

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.

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Accepted/In Press date: 9 February 2017
e-pub ahead of print date: 11 April 2017
Published date: 18 April 2017
Additional Information: Copyright © 2017 Elsevier Inc. All rights reserved.
Keywords: Journal Article

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Local EPrints ID: 414181
URI: http://eprints.soton.ac.uk/id/eprint/414181
ISSN: 1097-4180
PURE UUID: d1ce026a-27c4-4940-b43c-070657efe2ba

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Date deposited: 15 Sep 2017 16:31
Last modified: 23 Oct 2017 16:32

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Contributors

Author: Frederick Arce Vargas
Author: Andrew J.S. Furness
Author: Isabelle Solomon
Author: Kroopa Joshi
Author: Leila Mekkaoui
Author: Marta H. Lesko
Author: Enrique Miranda Rota
Author: Rony Dahan
Author: Andrew Georgiou
Author: Anna Sledzinska
Author: Assma Ben Aissa
Author: Dafne Franz
Author: Mariana Werner Sunderland
Author: Yien Ning Sophia Wong
Author: Jake Y. Henry
Author: Tim O'Brien
Author: David Nicol
Author: Ben Challacombe
Author: Samra Turajlic
Author: Martin Gore
Author: James Larkin
Author: Charles Swanton
Author: Kerry A Chester
Author: Martin Pule
Author: Jeffrey V. Ravetch
Author: Teresa Marafioti
Author: Karl S. Peggs
Author: Sergio A. Quezada

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