SATB1 is a targetable modulator of JAK-STAT signaling and cytokines in human Treg and Tconv cells.

The chromatin organizer SATB1 is indispensable for thymic regulatory T cell (Treg cell) development and T helper cell induction. Several gene loci have been described to be SATB1-controlled, including the transcription factor GATA3 and the cytokine loci IL-4 and IL-17. However, the global effects of SATB1 on fully differentiated human CD4 conventional T cells (Tconv cells) and Treg cells, and thus the potential of SATB1 as a target for T-cell engineering, are poorly understood. Here, we describe SATB1-regulated gene signatures as largely subset-specific, with broader effects on Treg cells. Despite distinct gene-regulatory patterns, we observe overarching dysregulated cytokine and JAK-STAT signaling after SATB1 ablation. Functionally, SATB1 KO reduces suppressive capacities of human Treg cells but boosts tumor clearance via CD4 CAR T cells in a preclinical, humanized mouse model. Taken together, Treg destabilization and simultaneous increased activation of CD4 CAR T cells by SATB1 modulation may be a strategy to boost the efficiency of CAR T cell therapies.