Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells

Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46+ inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression. [Display omitted] •Mature inflammatory dendritic cells (DCs) infiltrate solid ovarian cancers•Satb1 regulates the differentiation of conventional CD4+ DCs•Satb1 regulates Notch signaling, which turns on MHC II in inflammatory DCs•Unremitting expression of Satb1 drives immunosuppressive DCs Tesone et al. report that dynamic expression of Satb1 regulates the generation and immunostimulatory activity of conventional dendritic cells (DCs) and the acquisition of MHC II expression in inflammatory DCs. However, relentless Satb1 overexpression in tumor-associated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.