Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors
Frederick Arce Vargas(London Cancer), Andrew J.S. Furness(Royal Marsden NHS Foundation Trust), Isabelle Solomon(London Cancer), Kroopa Joshi(Royal Marsden NHS Foundation Trust), Leila Mekkaoui(CRUK Lung Cancer Centre of Excellence), Marta H. Lesko(London Cancer), Enrique Miranda(CRUK Lung Cancer Centre of Excellence), Rony Dahan(Rockefeller University), Andrew Georgiou(London Cancer), Anna Śledzińska(London Cancer), Assma Ben Aïssa(London Cancer), Dafne Franz(London Cancer), Mariana Werner Sunderland(London Cancer), Yien Ning Sophia Wong(London Cancer), Jake Y. Henry(London Cancer), Tim O’Brien(Guy's and St Thomas' NHS Foundation Trust), David Nicol(Royal Marsden NHS Foundation Trust), Ben Challacombe(Guy's and St Thomas' NHS Foundation Trust), Stephen A. Beers(University of Southampton), Samra Turajlic(Royal Marsden NHS Foundation Trust), Martin Gore(Royal Marsden NHS Foundation Trust), James Larkin(Royal Marsden NHS Foundation Trust), Charles Swanton(The Francis Crick Institute), Kerry Chester(CRUK Lung Cancer Centre of Excellence), Martin Pulé(CRUK Lung Cancer Centre of Excellence), Jeffrey V. Ravetch(Rockefeller University), Teresa Marafioti(University College Hospital), Karl S. Peggs(London Cancer), Sergio A. Quezada(London Cancer), Lavinia Spain, Andrew Wotherspoon(London Cancer), Steve Hazell, Myles Smith, D. Strauß, Andrew J. Hayes(London Cancer), Aspasia Soultati, Mark Stares(The Francis Crick Institute), Lavinia Spain, Joanna Lynch, Nicos Fotiadis, Archana Fernando, Steve Hazell, Ashish Chandra, Lisa Pickering, Sarah Rudman, Simon Chowdhury, Charles Swanton(The Francis Crick Institute), Mariam Jamal‐Hanjani, Selvaraju Veeriah, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard‐Carter, Gerald Goh, Rachel Rosenthal, Pat Gorman, Nirupa Murugaesu, Robert E. Hynds, Gareth A. Wilson, Nicolai J. Birkbak(Royal Marsden NHS Foundation Trust), Thomas B.K. Watkins, Nicholas McGranahan, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Peter Van Loo, Andrew Rowan(London Cancer), Hang Xu, Samra Turajlic(Royal Marsden NHS Foundation Trust), Crispin T. Hiley, Christopher Abbosh, Jacki Goldman, Richard Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward(London Cancer), Jennifer Biggs, Marta Costa(London Cancer), Sharmin Begum, Ben Phillimore(Guy's and St Thomas' NHS Foundation Trust), Tim Chambers(Guy's and St Thomas' NHS Foundation Trust), Emma Nye, Sofia Graca, Maise Al Bakir, John A. Hartley, Helen L. Lowe, Javier Herrero, David Lawrence(Royal Marsden NHS Foundation Trust), Dahmane Oukrif(CRUK Lung Cancer Centre of Excellence), Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky M. Thakrar, Martin Förster(CRUK Lung Cancer Centre of Excellence), Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, R. Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali N. Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, P. W. J. Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Philip Crosbie, Stuart Moss, Faiza Idries, Leena Dennis Joseph, Jane Rogan, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr(CRUK Lung Cancer Centre of Excellence), Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean A. Fennell, Jacqui Shaw, John Le Quesne, David A. Moore(Royal Marsden NHS Foundation Trust), Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, M. Nicolson, Keith M. Kerr(CRUK Lung Cancer Centre of Excellence), Shirley Palmer, Hardy Remmen, J. Richard Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, J.F. Lester, Alison Edwards, Fiona J. E. Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell(London Cancer), Natasha Iles, Allan Hackshaw, Yenting Ngai, Sean G. Smith, Nicole Gower, Christian H. Ottensmeier, Serena Chee, Benjamin M. Johnson, Aiman Alzetani, Emily Shaw, Eric Lim(London Cancer), Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jorda, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie M. Green, Hillaria Mashinga, Andrew G. Nicholson(London Cancer), Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Peter Russell, Teresa Light(University College Hospital), Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews(Royal Marsden NHS Foundation Trust), Yota Kitsanta(Royal Marsden NHS Foundation Trust), Kim Suvarna(Royal Marsden NHS Foundation Trust), Patricia Fisher(The Francis Crick Institute), Allah Dino Keerio(CRUK Lung Cancer Centre of Excellence), Michael Shackcloth(CRUK Lung Cancer Centre of Excellence), John R. Gosney(Rockefeller University), Pieter E. Postmus(University College Hospital), Sarah Feeney(Cancer Research UK), Julius Asante-Siaw(Cancer Research UK)
Cited by 428Open Access
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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