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

EBioMedicine | Nov 22, 2016

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.

Pubmed ID: 27769803 RIS Download

Mesh terms: Animals | Autoimmunity | Cell Line, Tumor | Disease Models, Animal | Forkhead Transcription Factors | Gene Expression | Histone Acetyltransferases | Immunity | Lymphocyte Activation | Mice | Mice, Knockout | Mice, Transgenic | Neoplasms | T-Lymphocyte Subsets | T-Lymphocytes, Regulatory | Trans-Activators | Tumor Burden | Ubiquitin-Specific Proteases

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Addgene

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