Inhibition of SUMOylation Elicits an Immune Response via Activation and Maturation of Dendritic Cells In Vitro

Abstract

This study investigates whether pharmacological inhibition of the SUMOylation pathway activates dendritic cells in vitro by stimulating Type I IFN responses. SUMOylation is a reversible post-translational protein modification by the Small Ubiquitin-like Modifier (SUMO) that regulates the activity of multiple cellular processes such as transcription, DNA repair, cell cycle, gene expression and antiviral defense (Adorisio et al., 2017; Gareau & Lima, 2010) . SUMOylation has been shown to negatively regulate innate immune responses. Impairing SUMOylation through a genetic ablation of the pathway by knocking out a key pathway enzyme, Ubc9, has shown to upregulate inflammatory cytokines and type I interferons considerably (Dejean et al., 2016). However, the Ubc9 knockout results in complete inhibition of SUMOylation, a method which may not be readily applicable to therapeutic intervention. Takeda has developed a small molecule inhibitor which blocks the SUMO cascade (He at al, 2017), and our goal is to determine whether pharmacological inhibition recapitulates the effects of knock out in stimulating Type I IFN responses in dendritic cells (DCs), providing therapeutic rationale for SUMO inhibitor drug development. Here we show that the small molecule SUMO inhibitor upregulated activation markers CD80, CD86, CD40 in both human and mice dendritic cells. We also observe an increase in pro-inflammatory cytokines and type I IFNs such as IFN-β. These data, taken together, provides strong evidence that inhibiting SUMOylation induces the activation of DCs via type I IFN responses which has been shown to be essential in adaptive immune response and anti-tumor immune response (Diamond et al., 2003; Corrales et al., 2017). Thus, pharmacological inhibition of SUMOylation pathway provides a novel immune therapy for cancer and other prevalent diseases.