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

Tom L. Stephen, Kyle K. Payne, Ricardo A. Chaurio, Michael J. Allegrezza, Hengrui Zhu, Jairo Perez-Sanz, Alfredo Perales-Puchalt, Jenny M. Nguyen, Ana E. Vara-Ailor, Evgeniy B. Eruslanov, Mark E. Borowsky, Rugang Zhang, Terri M. Laufer, Jose R. Conejo-Garcia

Research output: Contribution to journalArticlepeer-review

99 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)51-64
Number of pages14
Issue number1
StatePublished - Jan 17 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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