Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

WILLIAMS, G.S., MISTRY, B., GUILLARD, S., ULRICHSEN, J.C., SANDERCOCK, A.M., WANG, J., GONZÁLEZ-MUÑOZ, A., PARMENTIER, J., BLACK, C., SODEN, J., FREETH, J., JOVANOVIC, J., LEYLAND, Rebecca, AL-LAMKI, R.S., LEISHMAN, A.J., RUST, S.J., STEWART, R., JERMUTUS, L., BRADLEY, J.R., BEDIAN, V., VALGE-ARCHER, V., MINTER, R. and WILKINSON, R.W. (2016). Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy. Oncotarget, 7 (42), 68278-68291.

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© 2015. Oncotarget. 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 Teffcells, 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.

Item Type: Article
Uncontrolled Keywords: TNFR2; regulatory T cell; cancer immunotherapy; drug discovery; phenotypic screening; 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; Cell Line, Tumor; Jurkat Cells; Animals; Mice, Inbred BALB C; Humans; Neoplasms; Neoplasms, Experimental; NF-kappa B; Receptors, Tumor Necrosis Factor, Type II; Antineoplastic Agents; Immunotherapy; Drug Screening Assays, Antitumor; Signal Transduction; Phenotype; Female; T-Lymphocytes, Regulatory; HEK293 Cells
Identification Number:
Page Range: 68278-68291
SWORD Depositor: Symplectic Elements
Depositing User: Symplectic Elements
Date Deposited: 25 Mar 2019 16:47
Last Modified: 18 Mar 2021 06:21

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