Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.
Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.
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HDAC 基因的频繁扩增以及 HDAC 抑制剂西达本胺和 PD-1 阻断组合在软组织肉瘤中的疗效
DOI：
10.1136/jitc-2020-001696
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Que Y;Zhang XL;Liu ZX;Zhao JJ;Pan QZ;Wen XZ;Xiao W;Xu BS;Hong DC;Guo TH;Shen LJ;Fan WJ;Chen HY;Weng DS;Xu HR;Zhou PH;Zhang YZ;Niu XH;Zhang X
免疫检查点疗法的出现是癌症治疗的巨大进步。然而，软组织肉瘤（STS）患者的反应仍然不足。我们的目的是确定合理的组合，以增加对免疫检查点治疗的反应并提高生存率。方法对11例脂肪肉瘤患者进行全外显子序列分析。在基因水平上分析体细胞拷贝数改变（SCNAs），以确定药物靶基因中明显的扩增模式。在我们中心的49例肉瘤患者中评估了I类组蛋白脱乙酰酶（HDAC）的表达和预后价值，并在肿瘤癌症基因组图谱（TCGA）数据库中的263例肉瘤样本中得到证实。进行Q-PCR、流式细胞术和RNA-seq以确定I类HDAC、西达米特和PD-L1在体外和体内之间的相关性。在免疫活性小鼠模型和一小群晚期肉瘤患者中探索了西达米特与PD-1阻断剂联合使用的疗效。采用Western blot、ChIP法和双荧光素酶法研究其作用机制。结果HDAC基因家族在STS中扩增频率较高。基于药物靶基因集，HDAC基因家族中的SCNAs在11例脂肪肉瘤患者中的8例（73%）中广泛扩增，我们通过分析TCGA肉瘤队列证实了76.65%（197/257）的病例扩增。I类HDAC表达与STS患者的不良预后相关，并且其抑制负责促进细胞凋亡和上调程序性细胞死亡配体1（PD-L1）。HDAC I类抑制剂西达米特显著增加PD-L1表达，增加CD 8 + T细胞的浸润，并减少肿瘤微环境中MDSC的数量。西达米特与抗PD-1抗体的组合显著促进肿瘤消退并改善鼠模型中的存活率。此外，西达米特联合抗PD-1抗体toripalimab对晚期和转移性肉瘤患者有效，副作用可耐受。从机制上讲，西达米特通过激活转录因子STAT 1增加PD-L1基因处的组蛋白乙酰化。结论西达米特联合抗程序性细胞死亡1（PD-1）治疗STS是一种潜在的重要策略。
Background The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. Methods Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. Results The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. Conclusions The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.
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影响因子：
6.4
作者：
Kawai, H;Li, HC;Avraham, HK
通讯作者：
Avraham, HK
影响因子：
5.8
作者：
Briere, David;Sudhakar, Niranjan;Christensen, James G.
通讯作者：
Christensen, James G.
影响因子：
6.4
作者：
Muller, Christoph R.;Paulsen, Erik B.;Myklebost, Ola
通讯作者：
Myklebost, Ola
影响因子：
45.3
作者：
O'Connor, Owen A.;Horwitz, Steven;Shustov, Andrei
通讯作者：
Shustov, Andrei
影响因子：
--
作者：
Kroesen M;Gielen P;Brok IC;Armandari I;Hoogerbrugge PM;Adema GJ
通讯作者：
Adema GJ