| Title: |
Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy. |
| Authors: |
Williams, Geoffrey S; Mistry, Bina; Guillard, Sandrine; Ulrichsen, Jane Coates; Sandercock, Alan M; Wang, Jun; González-Muñoz, Andrea; Parmentier, Julie; Black, Chelsea; Soden, Jo; Freeth, Jim; Jovanović, Jelena; Leyland, Rebecca; Al-Lamki, Rafia S; Leishman, Andrew J; Rust, Steven J; Stewart, Ross; Jermutus, Lutz; Bradley, John R; Bedian, Vahe; Valge-Archer, Viia; Minter, Ralph; Wilkinson, Robert W |
| Publisher Information: |
Impact Journals; //www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=11943&path%5B%5D=37807 |
| Publication Year: |
2016 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
TNFR2; cancer immunotherapy; drug discovery; phenotypic screening; regulatory T cell; Animals; Antineoplastic Agents; Cell Line; Tumor; Drug Screening Assays; Antitumor; Female; HEK293 Cells; Humans; Immunotherapy; Jurkat Cells; Mice; Inbred BALB C; NF-kappa B; Neoplasms; Experimental; Phenotype; Receptors; Tumor Necrosis Factor; Type II; Signal Transduction; T-Lymphocytes; Regulatory |
| Description: |
Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery. ; GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/278311 |
| DOI: |
10.17863/CAM.24987 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/278311; https://doi.org/10.17863/CAM.24987 |
| Rights: |
Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.BAB21BD |
| Database: |
BASE |