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EBioMedicine. 2016 Nov;13:99-112. doi: 10.1016/j.ebiom.2016.10.018. Epub 2016 Oct 15.

Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity.

Author information

1
Division 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.
2
Progenra, Inc., Malvern, PA 19355, USA.
3
Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA.
4
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA19104, USA.
5
Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
6
Division 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. Electronic address: whancock@mail.med.upenn.edu.

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.

KEYWORDS:

Anti-tumor immunity; Deubiquitination; Immuno-oncology; T-regulatory cells

PMID:
27769803
PMCID:
PMC5264272
DOI:
10.1016/j.ebiom.2016.10.018
[Indexed for MEDLINE]
Free PMC Article

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