Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

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Williams, Geoffrey S 
Mistry, Bina 
Guillard, Sandrine 
Ulrichsen, Jane Coates 
Sandercock, Alan M 

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.

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, Neoplasms, Experimental, Phenotype, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, T-Lymphocytes, Regulatory
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Kidney Research UK (SP/GW1/2012)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-30)
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.