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

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

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.

MeSH terms

  • Animals
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression
  • Histone Acetyltransferases / metabolism*
  • Immunity
  • Lymphocyte Activation / immunology
  • Lysine Acetyltransferase 5
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Trans-Activators / metabolism*
  • Tumor Burden
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitin-Specific Proteases / antagonists & inhibitors*
  • Ubiquitin-Specific Proteases / genetics

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Trans-Activators
  • Histone Acetyltransferases
  • Kat5 protein, mouse
  • Lysine Acetyltransferase 5
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitin-Specific Proteases
  • Usp7 protein, mouse