Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Antibodies targeting T cells can improve anti-tumor immunity.
• Identifying new immunotherapy targets is crucial for cancer treatment.

Purpose of the Study:

• To discover novel cancer immunotherapy targets using phenotypic screening of regulatory T (Treg) cells.
• To investigate the role of tumor necrosis factor receptor 2 (TNFR2) as a potential immunotherapy target.

Main Methods:

• Phage display library screening to identify Treg-selective antibody mimetics.
• In vitro assays to assess TNFR2 agonism and downstream signaling (iκ-B degradation, NF-κB pathway).
• Analysis of TNFR2 expression in tumor-infiltrating T cells from lung cancer patients and in a mouse tumor model.

Main Results:

• Screening identified TNFR2 as a Treg-selective target.
• TNFR2 agonists were found to activate the receptor, inducing NF-κB signaling.
• TNFR2 is expressed on tumor-infiltrating Treg and T effector cells in lung cancer and mouse models.
• TNFR2 agonists inhibited tumor growth, increased CD8+ T cell infiltration, and enhanced IFN-γ production in vivo.

Conclusions:

• This study reveals a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy.
• TNFR2 is a promising target for developing new cancer immunotherapies.
• Target-agnostic screening is a valuable approach for identifying important drug discovery targets.