Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
Nat Cancer. 2023 Mar;4(3):382-400. doi: 10.1038/s43018-023-00522-1. Epub 2023 Mar 9.
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.
针对 PD-1/PD-L1 轴的免疫疗法已成为多种癌症的一线治疗方法。然而，由于调节 PD-1/PD-L1 的机制难以捉摸，只有有限的一部分人能获得持久的疗效。在这里，我们报告说，在暴露于干扰素-γ（IFNγ）的细胞中，KAT8 与诱导的 IRF1 发生相分离，并形成生物分子凝聚物以上调 PD-L1。IRF1 和 KAT8 之间特异性和混杂相互作用的多价性对于凝聚物的形成是必需的。KAT8-IRF1 凝聚促进了 IRF1 K78 的乙酰化和与 CD247（PD-L1）启动子的结合，并进一步丰富了转录装置，以促进 PD-L1 mRNA 的转录。基于 KAT8-IRF1 凝聚物形成的机制，我们鉴定了 2142-R8 阻断肽，该肽能破坏 KAT8-IRF1 凝聚物的形成，从而抑制 PD-L1 的表达，并增强体外和体内的抗肿瘤免疫。我们的研究结果揭示了 KAT8-IRF1 凝聚物在 PD-L1 调节中的关键作用，并提供了一种竞争肽来增强抗肿瘤免疫反应。
