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

TY - JOUR

T1 - SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells

AU - Stephen, Tom L.

AU - Payne, Kyle K.

AU - Chaurio, Ricardo A.

AU - Allegrezza, Michael J.

AU - Zhu, Hengrui

AU - Perez-Sanz, Jairo

AU - Perales-Puchalt, Alfredo

AU - Nguyen, Jenny M.

AU - Vara-Ailor, Ana E.

AU - Eruslanov, Evgeniy B.

AU - Borowsky, Mark E.

AU - Zhang, Rugang

AU - Laufer, Terri M.

AU - Conejo-Garcia, Jose R.

N1 - Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/1/17

Y1 - 2017/1/17

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85009517413

U2 - 10.1016/j.immuni.2016.12.015

DO - 10.1016/j.immuni.2016.12.015

M3 - Article

C2 - 28099864

SN - 1074-7613

VL - 46

SP - 51

EP - 64

JO - Immunity

JF - Immunity

IS - 1

ER -