title: SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells.
abstract: Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor β (Tgf-β) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Chaurio
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Hengrui
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jairo
authors.initials: J
authors.lastname: Perez-Sanz
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Ana E
authors.initials: AE
authors.lastname: Vara-Ailor
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Evgeniy B
authors.initials: EB
authors.lastname: Eruslanov
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Borowsky
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Terri M
authors.initials: TM
authors.lastname: Laufer
authors.affiliation: Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jose.conejo-garcia@moffitt.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D058501:Enzyme-Linked Immunospot Assay; D063185:Epigenetic Repression / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D036961:Matrix Attachment Region Binding Proteins / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis*
chemical_list: D036961:Matrix Attachment Region Binding Proteins; D061026:Programmed Cell Death 1 Receptor