title: Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity.
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.
authors: 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.
authors: Liqing
authors: L
authors: Wang
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Suresh
authors: S
authors: Kumar
authors: 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.
authors: Satinder
authors: S
authors: Dahiya
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Feng
authors: F
authors: Wang
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Jian
authors: J
authors: Wu
authors: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA.
authors: Kheng
authors: K
authors: Newick
authors: 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.
authors: Rongxiang
authors: R
authors: Han
authors: 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.
authors: Arabinda
authors: A
authors: Samanta
authors: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA19104, USA.
authors: Ulf H
authors: UH
authors: Beier
authors: 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.
authors: Tatiana
authors: T
authors: Akimova
authors: 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.
authors: Tricia R
authors: TR
authors: Bhatti
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Benjamin
authors: B
authors: Nicholson
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Mathew P
authors: MP
authors: Kodrasov
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Saket
authors: S
authors: Agarwal
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: David E
authors: DE
authors: Sterner
authors: Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors: Wei
authors: W
authors: Gu
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Joseph
authors: J
authors: Weinstock
authors: Progenra, Inc., Malvern, PA 19355, USA.
authors: Tauseef R
authors: TR
authors: Butt
authors: Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA.
authors: Steven M
authors: SM
authors: Albelda
authors: 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.
authors: Wayne W
authors: WW
authors: Hancock
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression; D051548:Histone Acetyltransferases / Q000378:metabolism*; D007109:Immunity; D008213:Lymphocyte Activation / Q000276:immunology; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D047368:Tumor Burden; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse
keywords: Anti-tumor immunity; Deubiquitination; Immuno-oncology; T-regulatory cells