Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity

Abstract

Immunotherapies targeting the PD-1/PD-L1 axis have become first-line treatments in multiple cancers. However, only a limited subset of individuals achieves durable benefits because of the elusive mechanisms regulating PD-1/PD-L1. Here, we report that in cells exposed to interferon-γ (IFNγ), KAT8 undergoes phase separation with induced IRF1 and forms biomolecular condensates to upregulate PD-L1. Multivalency from both the specific and promiscuous interactions between IRF1 and KAT8 is required for condensate formation. KAT8–IRF1 condensation promotes IRF1 K78 acetylation and binding to the CD247 (PD-L1) promoter and further enriches the transcription apparatus to promote transcription of PD-L1 mRNA. Based on the mechanism of KAT8–IRF1 condensate formation, we identified the 2142–R8 blocking peptide, which disrupts KAT8–IRF1 condensate formation and consequently inhibits PD-L1 expression and enhances antitumor immunity in vitro and in vivo. Our findings reveal a key role of KAT8–IRF1 condensates in PD-L1 regulation and provide a competitive peptide to enhance antitumor immune responses.

Nucleic acid-sensing-related gene signature in predicting prognosis and treatment efficiency of small cell lung cancer patients

“…Moreover, the patients with lower 7NAS risk scores have a better response to immunotherapy and commonly have a long overall survival time compared to the patients high 7NAS risk scores underwent immunotherapy. IRF1 is the key transcription factor downstream of IFNg which can be induced by STAT1 (30,31). Here, in this study we demonstrated that IRF1 was most strongly correlated with the infiltration and functional roles of immune cells, suggesting it could serve as a potential target for enhancing the effectiveness of immunotherapy for SCLC patients.…”

cGAS: action in the nucleus

“…Third, it’s now well accepted that the enzymatic activity of cGAS can be inhibited by binding to chromatin nucleosome in the nucleus ( 14 ), however, whether cGAS participates in transcriptional regulation through modulating chromatin accessibility is unknown. LLPS has been previously reported to be important for regulating the activity of transcriptional factors such as IRF1 ( 129 ), and cGAS is capable of forming LLPS ( 23 ). Therefore, it’s interesting to question whether LLPS of cGAS serves as a mechanism underlying transcriptional regulation.…”

Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma

“…Following procedures as previously described ( 71 ). To label L3MBTL2-interacting proteins, doxycycline-inducible Flag-Bio-ID-L3MBTL2–expressing U2OS stable cells were treated with doxycycline (200 ng/ml) for 24 hours.…”