Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity
Liqing Wang,
Suresh Kumar,
Satinder Dahiya,
Feng Wang,
Jian Wu,
Kheng Newick,
Rongxiang Han,
Arabinda Samanta,
Ulf H. Beier,
Tatiana Akimova,
Tricia R. Bhatti,
Benjamin Nicholson,
Mathew P. Kodrasov,
Saket Agarwal,
David E. Sterner,
Wei Gu,
Joseph Weinstock,
Tauseef R. Butt,
Steven M. Albelda,
Wayne W. Hancock
Affiliations
Liqing Wang
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
Suresh Kumar
Progenra, Inc., Malvern, PA 19355, USA
Satinder Dahiya
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
Feng Wang
Progenra, Inc., Malvern, PA 19355, USA
Jian Wu
Progenra, Inc., Malvern, PA 19355, USA
Kheng Newick
Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA
Rongxiang Han
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
Arabinda Samanta
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
Ulf H. Beier
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA19104, USA
Tatiana Akimova
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
Tricia R. Bhatti
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
Benjamin Nicholson
Progenra, Inc., Malvern, PA 19355, USA
Mathew P. Kodrasov
Progenra, Inc., Malvern, PA 19355, USA
Saket Agarwal
Progenra, Inc., Malvern, PA 19355, USA
David E. Sterner
Progenra, Inc., Malvern, PA 19355, USA
Wei Gu
Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Joseph Weinstock
Progenra, Inc., Malvern, PA 19355, USA
Tauseef R. Butt
Progenra, Inc., Malvern, PA 19355, USA
Steven M. Albelda
Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA
Wayne W. Hancock
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
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.
