Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis.
Kei-Ichiro ArimotoSayuri MiyauchiTy D TroutmanYue ZhangMengdan LiuSamuel A StonerAmanda G DavisJun-Bao FanYi-Jou HuangMing YanChristopher K GlassDong-Er ZhangPublished in: Nature communications (2023)
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.
Keyphrases
- immune response
- dendritic cells
- papillary thyroid
- cancer therapy
- poor prognosis
- cell death
- squamous cell
- genome wide
- signaling pathway
- end stage renal disease
- binding protein
- chronic kidney disease
- ejection fraction
- transcription factor
- squamous cell carcinoma
- genome wide identification
- long non coding rna
- dna methylation
- newly diagnosed
- mouse model
- gene expression
- nlrp inflammasome
- inflammatory response
- small molecule
- risk assessment
- prognostic factors
- cell proliferation
- young adults
- pi k akt
- protein kinase
- anti inflammatory
- induced pluripotent stem cells