Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma
| Autor: | Tian-Hui Guo, Xizhi Wen, Lujun Shen, Dongchun Hong, Wei-Jun Fan, Xiao-Long Zhang, Yizhuo Zhang, Qiu-Zhong Pan, Xiao-Hui Niu, Xing Zhang, Bu-Shu Xu, De-Sheng Weng, Jing Jing Zhao, Yi Que, Penghui Zhou, Huoying Chen, Wei Xiao, Zexian Liu, Hai-Rong Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
sarcoma Immunology Programmed Cell Death 1 Receptor Aminopyridines Histone Deacetylase 2 Histone Deacetylase 1 B7-H1 Antigen Histone Deacetylases chemistry.chemical_compound Mice Chidamide Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Exome Sequencing medicine Immunology and Allergy Animals Humans STAT1 Immune Checkpoint Inhibitors RC254-282 Pharmacology Clinical/Translational Cancer Immunotherapy Tumor microenvironment biology business.industry Sequence Analysis RNA Soft tissue sarcoma Gene Expression Profiling Gene Amplification Neoplasms. Tumors. Oncology. Including cancer and carcinogens Liposarcoma medicine.disease Xenograft Model Antitumor Assays Immune checkpoint Gene Expression Regulation Neoplastic Histone Oncology chemistry Benzamides biology.protein Cancer research Molecular Medicine Sarcoma business CD8 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 2 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | BackgroundThe 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.MethodsWhole-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.ResultsThe 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.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS. |
| Databáze: | OpenAIRE |
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