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

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Vargas, Frederick Arce, Furness, Andrew JS, Solomon, Isabelle, Joshi, Kroopa, Mekkaoui, Leila, Lesko, Marta H, Rota, Enrique Miranda, Dahan, Rony, Georgiou, Andrew, Sledzinska, Anna et al (show 19 more authors) , Ben Aissa, Assma, Franz, Dafne, Sunderland, Mariana Werner, 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 (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.

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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.

Item Type:	Article
Uncontrolled Keywords:	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
Depositing User:	Symplectic Admin
Date Deposited:	23 Jan 2019 15:01
Last Modified:	05 Feb 2023 17:42
DOI:	10.1016/j.immuni.2017.03.013
Open Access URL:	https://reader.elsevier.com/reader/sd/pii/S1074761...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3031694