Search

While immunotherapy has emerged as a breakthrough cancer therapy, it is only effective in some patients, indicating the need of alternative therapeutic strategies. Induction of cancer immunogenic cell death (ICD) is one promising way to elicit potent adaptive immune responses against tumor-associated antigens. Type I interferon (IFN) is well known to play important roles in different aspects of immune responses, including modulating ICD in anti-tumor action. However, how to expand IFN effect in promoting ICD responses has not been addressed. Here we show that depletion of ubiquitin specific protease 18 (USP18), a negative regulator of IFN signaling, selectively induces cancer cell ICD. Lower USP18 expression correlates with better survival across human selected cancer types and delays cancer progression in mouse models. Mechanistically, nuclear USP18 controls the enhancer landscape of cancer cells and diminishes STAT2-mediated transcription complex binding to IFN-responsive elements. Consequently, USP18 suppression not only enhances expression of canonical IFN-stimulated genes (ISGs), but also activates the expression of a set of atypical ISGs and NF-κB target genes, including genes such as Polo like kinase 2 (PLK2), that induce cancer pyroptosis. These findings may support the use of targeting USP18 as a potential cancer immunotherapy.

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/− cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/− cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/− animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/− adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.