BAP1 可调节胰腺癌中 HSF1 的活性和癌症免疫。

IF 11.4 1区 医学 Q1 ONCOLOGY
Weiwei Yuan, Qiyue Zhang, Yuhan Zhao, Wentao Xia, Shilin Yin, Xueyi Liang, Taoyu Chen, Gaofeng Li, Yanshen Liu, Zhiqiang Liu, Jinxi Huang
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引用次数: 0

摘要

背景:绝大多数胰腺癌已被证明对单药剂免疫疗法不敏感。探索免疫耐受的机制并实施联合治疗策略对于PDAC患者从免疫疗法中获益至关重要。约27%的PDAC患者存在BAP1缺失,且与预后不良显著相关,但BAP1缺失如何影响PDAC患者生存的机制仍是一个谜:方法:应用BAP1基因敲除KPC(KrasG12D/+; LSLTrp53R172H/+; Pdx-1-Cre)小鼠和对照KPC小鼠、合成异种移植模型分析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,揭示了潜在的机制。研究人员构建了合成异种移植模型和流式细胞术,以检测SIRT1抑制剂的疗效及其与抗PD-1疗法的协同作用:结果:BAP1的缺失导致了PDAC对免疫疗法的耐药性,这是由于BAP1抑制了HSF1的转录活性。具体来说,BAP1与SIRT1竞争结合到K80乙酰化的HSF1上。BAP1 与 HSF1 的相互作用保留了 HSF1-K80 的乙酰化,并促进了 HSF1-HSP70 的相互作用,从而促进了 HSF1 的寡聚化和与染色质的分离。此外,我们还证明了靶向抑制 SIRT1 可逆转 BAP1 缺乏的 PDAC 小鼠模型的免疫不敏感性:我们的研究阐明了 BAP1 通过抑制 HSF1 调节 PDAC 免疫治疗反应的一种尚未揭示的机制,并为解决 BAP1 缺乏型 PDAC 的免疫不敏感问题提供了有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
BAP1 regulates HSF1 activity and cancer immunity in pancreatic cancer.

Background: 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.

Methods: 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.

Result: 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.

Conclusion: 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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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