<br>HDAC5 通过 p65 去乙酰化在胰腺癌中调节 PD-L1 表达和癌症免疫。,Theranostics

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HDAC5 通过 p65 去乙酰化在胰腺癌中调节 PD-L1 表达和癌症免疫。
Theranostics ( IF 12.4 ) Pub Date : 2022-01-31 , DOI: 10.7150/thno.69444
Yingke Zhou _{1,

2} , Xin Jin _{3,

4} , Haixin Yu ₅ , Gengdu Qin _{1,

2} , Penglin Pan _{1,

2} , Jingyuan Zhao _{1,

2} , Taoyu Chen _{1,

2} , Xueyi Liang _{1,

2} , Yan Sun _{1,

2} , Bo Wang _{1,

2} , Dianyun Ren _{1,

2} , Shikai Zhu ₆ , Heshui Wu _{1,

2}

Affiliation

理由：胰腺导管腺癌 (PDAC) 是一种致命疾病，5 年生存率不足 10%。大多数 PDAC 患者对单药免疫治疗反应不佳。迫切需要针对免疫疗法耐药机制的多模式疗法。我们发现 IIa 类组蛋白脱乙酰酶 (HDAC) 成员 HDAC5 在多种实体瘤中下调，其水平与 PDAC 患者的良好预后相关。在癌症基因组图谱 (TCGA) 胰腺癌数据集中，HDAC5 缺失患者的上调基因在适应性免疫反应和淋巴细胞介导的免疫中丰富。方法：利用胰腺癌组织芯片分析HDAC5与PD-L1的相关性。通过RNA-seq、转录因子基序分析、药物筛选和分子生物学测定来确定HDAC5抑制PD-L1的机制。应用小鼠胰腺癌同种异体移植物来测试 HDAC5 抑制和抗 PD1 联合治疗的效率。结果：HDAC5通过直接与NF-κB p65相互作用调节PD-L1表达；这种相互作用被 p65 丝氨酸 311 磷酸化所抑制。此外，HDAC5 减少了 p65 赖氨酸 310 处的乙酰化，这对于 p65 的转录活性至关重要。重要的是，我们在同系小鼠模型和 KPC 小鼠衍生的 PDAC 模型中证明，HDAC5 沉默或抑制使 PDAC 肿瘤对免疫检查点阻断 (ICB) 疗法敏感。结论：我们的研究结果揭示了 HDAC5 在调节 NF-κB 信号通路和抗肿瘤免疫反应中的先前未知的作用。这些发现为通过抑制 HDAC5 来增强 ICB 在免疫治疗耐药性 PDAC 中的抗肿瘤作用提供了强有力的理论依据。

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HDAC5 modulates PD-L1 expression and cancer immunity via p65 deacetylation in pancreatic cancer.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal 5-year survival less than 10%. Most patients with PDAC exhibit poor response to single-agent immunotherapy. Multimodal therapies targeting mechanisms of resistance to immunotherapy are urgently needed. We found that the class IIa histone deacetylase (HDAC) member, HDAC5 is downregulated in multiple solid tumors and its level were associated with favorable prognosis in PDAC patients. Upregulated genes in patients harboring HDAC5 deletions were enriched in adaptive immune responses and lymphocyte-mediated immunity in The Cancer Genome Atlas (TCGA) pancreatic cancer dataset. Methods: Tissue microarray of pancreatic cancer were used to analysis the correlation between HDAC5 and PD-L1. RNA-seq, transcription factor motif analysis, drug screening and molecular biology assays were performed to identify the mechanism of HDAC5's repression on PD-L1. Allografts of pancreatic cancer in mouse were applied to test the efficiency of HDAC5 inhibition and anti-PD1 co-treatment. Results: HDAC5 regulated PD-L1 expression by directly interacting with NF-κB p65; this interaction was suppressed by p65 phosphorylation at serine-311. Additionally, HDAC5 diminished p65 acetylation at lysine-310, which is essential for the transcriptional activity of p65. Importantly, we demonstrated that HDAC5 silencing or inhibition sensitized PDAC tumors to immune checkpoint blockade (ICB) therapy in syngeneic mouse model and KPC mouse derived PDAC model. Conclusion: Our findings revealed a previously unknown role of HDAC5 in regulating the NF-κB signaling pathway and antitumor immune responses. These findings provide a strong rationale for augment the antitumor effects of ICB in immunotherapy-resistant PDAC by inhibiting HDAC5.

更新日期：2022-01-31

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