Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence un mécanisme par lequel l'acétyltransférase KAT8 et le facteur IRF1, en présence d'interféron gamma, forment un condensat biomoléculaire qui favorise l'expression du ligand PD-L1, puis identifie un peptide qui inhibe cette expression et augmente l'immunité antitumorale en entravant l'interaction entre KAT8 et IRF1
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.
Nature Cancer , article en libre accès, 2023