SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells

Immunity. 2017 Jan 17;46(1):51-64. doi: 10.1016/j.immuni.2016.12.015.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Enzyme-Linked Immunospot Assay
  • Epigenetic Repression / immunology*
  • Gene Expression Regulation / immunology*
  • Humans
  • Immunoprecipitation
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Matrix Attachment Region Binding Proteins / biosynthesis*
  • Matrix Attachment Region Binding Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Programmed Cell Death 1 Receptor / biosynthesis*


  • Matrix Attachment Region Binding Proteins
  • Programmed Cell Death 1 Receptor