The chromatin organizer SATB1 governs the epigenetic repression of the co-inhibitory receptor PD-1 in T cells

Abstract

Abstract Despite the importance of Programmed Cell Death-1 (PDCD1/PD-1) in inhibiting T-cell effector activity, the mechanisms regulating its expression in anti-tumor lymphocytes remain poorly defined. Here we show that the chromatin organizer Special AT-rich Sequence-Binding Protein-1 (Satb1) is required to restrain activation-induced PD-1 expression. We demonstrate that, mechanistically, Satb1 physically interacts with a nucleosome remodeling deacetylase (NuRD) complex, which it recruits to Pdcd1 regulatory regions. This molecular complex thus drives histone de-acetylation and results in PD-1 repression in T cells. Accordingly, T-cell-specific Satb1 deficiency results in a 40-fold increase in PD-1 expression. Intriguingly, tumor-derived Transforming growth factor (Tgf)-β decreases Satb1 expression in T cells through binding of Smad Family Member (Smad) proteins to the Satb1 promoter, while Smad also competes with Satb1/NuRD for binding to Pdcd1 enhancers, cooperatively unleashing PD-1 expression in a Satb1-dependent manner. Consequently, Satb1-deficient tumor-reactive T cells lose their effector activity more rapidly than wild-type T cells at PD-L1+ tumor beds, but these differences are abrogated by sustained PD-L1 blockade. Therefore, we demonstrate that Satb1 is an epigenetic controller of PD-1 expression, and that Tgf-β signaling contributes to T cell dysfunction within the tumor microenvironment by inhibiting Satb1-mediated repression of PD-1.