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Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes
Liqing Wang1, Suresh Kumar2, Satinder Dahiya1
1Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3+ Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.
Insights
Targeting Usp7 inhibits Foxp3+ T-regulatory (Treg) cell function, crucial for tumor growth. Usp7 inhibitors limit tumor progression and enhance cancer immunotherapy efficacy in preclinical models.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Foxp3+ T-regulatory (Treg) cells suppress anti-tumor immunity.
- Current Treg therapies have limitations, focusing on transient depletion or secondary modulation.
- Tip60, a histone acetyltransferase, is critical for Treg cell function.
Purpose of the Study:
- Investigate the role of ubiquitin-specific protease 7 (Usp7) in Treg cell function.
- Determine if targeting Usp7 can impair Treg suppressive activity and enhance anti-tumor responses.
Main Methods:
- Studied post-translational modifications regulating Foxp3.
- Utilized genetic and pharmacologic targeting of Usp7 in mouse models.
- Assessed Treg cell function, tumor growth, and efficacy of immunotherapy (anti-PD1).
Main Results:
- Usp7 stabilizes and promotes multimerization of Tip60 and Foxp3, thereby controlling Treg function.
- Genetic or pharmacologic inhibition of Usp7 impairs Treg suppressive functions without affecting conventional T cells.
- Usp7 inhibitors reduced tumor growth and enhanced the efficacy of antitumor vaccines and anti-PD1 therapy in mice.
Conclusions:
- Usp7 is a key regulator of Foxp3+ Treg cell stability and function.
- Pharmacologic targeting of Usp7 represents a promising strategy for cancer immunotherapy.
- Usp7 inhibitors may improve outcomes for patients undergoing cancer treatment.
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