Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.
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.
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Geoffrey S
GS
Williams
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Bina
B
Mistry
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Sandrine
S
Guillard
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Jane Coates
JC
Ulrichsen
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Alan M
AM
Sandercock
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Jun
J
Wang
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Andrea
A
González-Muñoz
Oncology iMED, AstraZeneca-R&D Boston, Waltham, MA 02451, USA.
Julie
J
Parmentier
MedImmune LLC, Gaithersburg, MD 20878, USA.
Chelsea
C
Black
Retrogenix Ltd, Whaley Bridge, High Peak, SK23 7LY, UK.
Jo
J
Soden
Retrogenix Ltd, Whaley Bridge, High Peak, SK23 7LY, UK.
Jim
J
Freeth
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Jelena
J
Jovanović
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Rebecca
R
Leyland
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Rafia S
RS
Al-Lamki
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Andrew J
AJ
Leishman
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Steven J
SJ
Rust
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Ross
R
Stewart
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Lutz
L
Jermutus
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
John R
JR
Bradley
Oncology iMED, AstraZeneca-R&D Boston, Waltham, MA 02451, USA.
Vahe
V
Bedian
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Viia
V
Valge-Archer
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Ralph
R
Minter
MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Robert W
RW
Wilkinson
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010641:Phenotype; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D047889:Receptors, Tumor Necrosis Factor, Type II
TNFR2; cancer immunotherapy; drug discovery; phenotypic screening; regulatory T cell