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
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View all literature mentionsSoftware providing a workbench for visualization, analysis and storage of microarray data. It features a graphical user interface and supports the development and integration of existing and new analysis methods. Besides the infrastructural core functionality, Mayday offers a variety of plug-ins, such as various interactive viewers, a connection to the R statistical environment, a connection to SQL-based databases, and different clustering methods, including phylogenetic methods. In addition, so-called meta information objects are provided for annotation of the microarray data allowing integration of data from different sources. This meta information can be used to enhance visualizations, such as in the enhanced heatmap visualization. Written in the Java programming language, Mayday is extremely portable and runs on all platforms supporting the Java runtime environment 1.6.
View all literature mentionslaboratory mouse with name BALB/cAnNCrl from MGI.
View all literature mentionsMus musculus with name B6.129(Cg)-Foxp3tm4(YFP/icre)Ayr/J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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