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Updated: Jun 29, 2026
Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
Published on: August 13, 2013
Identification of a group of 9-amino-acridines that selectively downregulate regulatory T cell functions through
Qian Wei1,2, Håvard Foyn1, Johannes Landskron3
1Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
Abstract:
FoxP3+ regulatory T cells (Tregs) are responsible for immune homeostasis by suppressing excessive anti-self-immunity. Tregs facilitate tumor growth by inhibiting anti-tumor immunity. Here, we explored the targeting of FoxP3 as a basis for new immunotherapies. In a high-throughput phenotypic screening of a drug repurposing library using human primary T cells, we identified quinacrine as a FoxP3 downregulator. In silico searches based on the structure of quinacrine, testing of sub-libraries of analogs in vitro, and validation identified a subset of 9-amino-acridines that selectively abrogated Treg suppressive functions. Mechanistically, these acridines interfered with the DNA-binding activity of FoxP3 and inhibited FoxP3-regulated downstream gene regulation. Release from Treg suppression by 9-amino-acridines increased anti-tumor immune responses both in cancer patient samples and in mice in a syngeneic tumor model. Our study highlights the feasibility of screening for small molecular inhibitors of FoxP3 as an approach to pursuing Treg-based immunotherapy.
Insights
Researchers identified 9-amino-acridines that inhibit FoxP3+ regulatory T cells (Tregs). This approach shows promise for Treg-based immunotherapy by enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- FoxP3+ regulatory T cells (Tregs) maintain immune homeostasis but can hinder anti-tumor immunity, promoting tumor growth.
- Targeting FoxP3 presents a potential strategy for novel immunotherapies.
- Understanding Treg function is crucial for developing effective cancer treatments.
Purpose of the Study:
- To explore the targeting of FoxP3 as a basis for new immunotherapies.
- To identify small molecules that can downregulate FoxP3 and abrogate Treg suppressive functions.
- To evaluate the potential of inhibiting Tregs to enhance anti-tumor immune responses.
Main Methods:
- High-throughput phenotypic screening of a drug repurposing library using human primary T cells.
- In silico analysis and in vitro testing of quinacrine analogs (9-amino-acridines).
- Mechanistic studies on the interference with FoxP3 DNA-binding activity and gene regulation.
- Validation in cancer patient samples and a syngeneic mouse tumor model.
Main Results:
- Quinacrine was identified as a FoxP3 downregulator.
- A subset of 9-amino-acridines selectively abrogated Treg suppressive functions by inhibiting FoxP3 DNA-binding.
- 9-amino-acridines enhanced anti-tumor immune responses in both human cancer samples and a mouse model.
- Release from Treg suppression led to increased anti-tumor immunity.
Conclusions:
- Screening for small molecular inhibitors of FoxP3 is a feasible approach for Treg-based immunotherapy.
- 9-amino-acridines represent a promising class of compounds for modulating Treg function.
- Targeting FoxP3 offers a viable strategy to overcome immune suppression in cancer and enhance therapeutic efficacy.
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