Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
J Exp Clin Cancer Res. 2024 Sep 30;43(1):275. doi: 10.1186/s13046-024-03196-4.
The vast majority of pancreatic cancers have been shown to be insensitive to single-agent immunotherapy. Exploring the mechanisms of immune resistance and implementing combination therapeutic strategies are crucial for PDAC patients to derive benefits from immunotherapy. Deletion of BAP1 occurs in approximately 27% of PDAC patients and is significantly correlated with poor prognosis, but the mechanism how BAP1-deletion compromises survival of patients with PDAC remain a puzzle.
Bap1 knock-out KPC (KrasG12D/+; LSLTrp53R172H/+; Pdx-1-Cre) mice and control KPC mice, syngeneic xenograft models were applied to analysis the correlation between BAP1 and immune therapy response in PDAC. Immunoprecipitation, RT-qPCR, luciferase and transcriptome analysis were combined to revealing potential mechanisms. Syngeneic xenograft models and flow cytometry were constructed to examine the efficacy of the inhibitor of SIRT1 and its synergistic effect with anti-PD-1 therapy.
The deletion of BAP1 contributes to the resistance to immunotherapy in PDAC, which is attributable to BAP1's suppression of the transcriptional activity of HSF1. Specifically, BAP1 competes with SIRT1 for binding to the K80 acetylated HSF1. The BAP1-HSF1 interaction preserves the acetylation of HSF1-K80 and promotes HSF1-HSP70 interaction, facilitating HSF1 oligomerization and detachment from the chromatin. Furthermore, we demonstrate that the targeted inhibition of SIRT1 reverses the immune insensitivity in BAP1 deficient PDAC mouse model.
Our study elucidates an unrevealed mechanism by which BAP1 regulates immune therapy response in PDAC via HSF1 inhibition, and providing promising therapeutic strategies to address immune insensitivity in BAP1-deficient PDAC.
绝大多数胰腺癌对单药免疫治疗不敏感。探索免疫抵抗的机制并实施联合治疗策略对于从免疫治疗中获益的 PDAC 患者至关重要。大约 27%的 PDAC 患者存在 BAP1 缺失，并且与预后不良显著相关，但 BAP1 缺失如何影响 PDAC 患者的生存仍不清楚。
应用 Bap1 敲除 KPC（KrasG12D/+；LSLTrp53R172H/+；Pdx-1-Cre）小鼠和对照 KPC 小鼠、同基因异种移植模型，分析 BAP1 与 PDAC 免疫治疗反应的相关性。免疫沉淀、RT-qPCR、荧光素酶和转录组分析相结合，揭示潜在的机制。构建同基因异种移植模型和流式细胞术，检测 SIRT1 抑制剂的疗效及其与抗 PD-1 治疗的协同作用。
BAP1 的缺失导致 PDAC 对免疫治疗产生耐药性，这归因于 BAP1 抑制了 HSF1 的转录活性。具体来说，BAP1 与 SIRT1 竞争结合 K80 乙酰化的 HSF1。BAP1-HSF1 相互作用保留了 HSF1-K80 的乙酰化，并促进了 HSF1-HSP70 相互作用，促进了 HSF1 寡聚化并从染色质上脱离。此外，我们证明靶向抑制 SIRT1 可逆转 BAP1 缺失 PDAC 小鼠模型中的免疫不敏感。
本研究通过 HSF1 抑制阐明了 BAP1 调节 PDAC 免疫治疗反应的未被揭示的机制，并为解决 BAP1 缺失 PDAC 的免疫不敏感提供了有前景的治疗策略。
