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Cancer Cell. 2018 Apr 9;33(4):649-663.e4. doi: 10.1016/j.ccell.2018.02.010. Epub 2018 Mar 22.

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

Collaborators (223)

Harrington K, Melcher A, Wotherspoon A, Francis N, Challacombe B, Fernando A, Hazell S, Chandra A, Pickering L, Lynch J, Rudman S, Chowdhury S, Harrison-Phipps K, Varia M, Horsfield C, Polson A, Stamp G, O'Donnell M, Drake W, Hill P, Hrouda D, Mayer E, Olsburgh J, Kooiman G, O'Connor K, Stewart G, Aitchison M, Tran M, Fotiadis N, Verma H, Lopez J, Lester J, Morgan F, Kornaszewska M, Attanoos R, Adams H, Davies H, Fennell D, Shaw J, Le Quesne J, Nakas A, Rathinam S, Monteiro W, Marshall H, Nelson L, Bennett J, Riley J, Primrose L, Martinson L, Anand G, Khan S, Nicolson M, Kerr K, Palmer S, Remmen H, Miller J, Buchan K, Chetty M, Gomersall L, Lock S, Naidu B, Langman G, Trotter S, Bellamy M, Bancroft H, Kerr A, Kadiri S, Webb J, Middleton G, Djearaman M, Summers Y, Califano R, Taylor P, Shah R, Krysiak P, Rammohan K, Fontaine E, Booton R, Evison M, Crosbie P, Moss S, Idries F, Novasio J, Joseph L, Bishop P, Chaturvedi A, Marie Quinn A, Doran H, Leek A, Harrison P, Moore K, Waddington R, Blackhall F, Rogan J, Smith E, Dive C, Brady G, Rothwell D, Gulati S, Chemie F, Tugwood J, Pierce J, Lawrence D, Hayward M, Panagiotopoulos N, George R, Patrini D, Falzon M, Borg E, Khiroya R, Jamal-Hanjani M, Wilson G, Juul Birkbak N, Watkins T, McGranahan N, Abbosh C, Horswell S, Mitter R, Escudero M, Stewart A, Rowan A, Hiley C, Goldman J, Ahmed A, Taylor M, Choudhary J, Shaw P, Veeriah R, Czyzewska-Khan J, Johnson D, Laycock J, Hynds R, Werner Sunderland M, Reading J, Novelli M, Oukrif D, Janes S, Forster M, Ahmad T, Ming Lee S, van Loo P, Herrero J, Hartley J, Kevin Stone R, Denner T, Costa M, Begum S, Phillimore B, Chambers T, Nye E, Ward S, Elgar G, Al-Bakir M, Carnell D, Mendes R, George J, Navani N, Papadatos-Pastos D, Scarci M, Gorman P, Lowe H, Ensell L, Moore D, MacKenzie M, Wilcox M, Bell H, Hackshaw A, Ngai Y, Smith S, Gower N, Ottensmeier C, Chee S, Johnson B, Alzetani A, Shaw E, Lim E, De Sousa P, Tavares Barbosa M, Nicholson A, Bowman A, Jordan S, Rice A, Raubenheimer H, Proli C, Elena Cufari M, Carlo Ronquillo J, Kwayie A, Bhayani H, Hamilton M, Bakar Y, Mensah N, Ambrose L, Devaraj A, Buderi S, Finch J, Azcarate L, Chavan H, Green S, Mashinga H, Lau K, Sheaff M, Schmid P, Conibear J, Ezhil V, Prakash V, Danson S, Bury J, Edwards J, Hill J, Matthews S, Kitsanta Y, Suvarna K, Shackcloth M, Gosney J, Postmus P, Feeney S, Asante-Siaw J, Russell P, Light T, Horey T, Blyth K, Dick C, Kirk A.

Author information

1
Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK.
2
Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK; The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
3
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
4
Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6DD, UK.
5
The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
6
Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK.
7
BioInvent International AB, 223 70 Lund, Sweden.
8
Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK.
9
Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK.
10
The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
11
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6DD, UK; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London WC1E 6DD, UK.
12
Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: k.peggs@ucl.ac.uk.
13
Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk.

Abstract

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

KEYWORDS:

CTLA-4; Fc-gamma receptors; IgG subclass; antibody-dependent cell-mediated cytotoxicity; immune checkpoints; immune regulatory antibodies; ipilimumab; regulatory T cell depletion; tremelimumab; tumor immunotherapy

PMID:
29576375
PMCID:
PMC5904288
DOI:
10.1016/j.ccell.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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