Arce Vargas, F., Furness, A.J.S., Litchfield, K. et al. (249 more authors) (2018) Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell, 33 (4). 649-663.e4. ISSN 1535-6108
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0) . |
Keywords: | CTLA-4; Regulatory T cell depletion; Ipilimumab; Tremelimumab; Antibody-dependent cell-mediated cytotoxicity; Fc-gamma receptors; IgG subclass; Immune checkpoints; Tumor immunotherapy; Immune regulatory antibodies |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Feb 2019 14:48 |
Last Modified: | 06 Feb 2019 14:48 |
Published Version: | https://doi.org/10.1016/j.ccell.2018.02.010 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.ccell.2018.02.010 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:142184 |
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Filename: Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.pdf
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