[PDF][PDF] SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells

TL Stephen, KK Payne, RA Chaurio, MJ Allegrezza… - Immunity, 2017 - cell.com
TL Stephen, KK Payne, RA Chaurio, MJ Allegrezza, H Zhu, J Perez-Sanz, A Perales-Puchalt
Immunity, 2017cell.com
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) …
Summary
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.
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