Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

Llópiz, Diana; Ruiz, Marta; Villanueva, Lorea; Iglesias, Tamara; Silva, Leyre; Egea, Josune; Lasarte, Juan José; Pivette, Perrine; Trochon-Joseph, Véronique; Vasseur, B.; Dixon, Graham; Sangro, Bruno; Sarobe, Pablo

doi:10.1007/s00262-018-2283-0

Cited by 107 publications

(65 citation statements)

References 58 publications

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“…Moreover, since our results potentially link the NuRD complex to immune infiltration in hepatocellular carcinoma, targeting the HDAC activity within the NuRD complex may synergize with immune checkpoint inhibitor treatment. In line with this hypothesis, there is evidence showing that HDAC inhibitor treatment indeed enhanced anti-tumor efficacy of checkpoint inhibitors in hepatocellular carcinoma [27]. As a chromatin remodeling enzyme subunit in the NuRD complex, CHD4 is pivotal to the chromatin remodeling activity of the complex as well as its ability in regulating target gene expression.…”

Section: Discussionmentioning

confidence: 80%

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma

et al. 2020

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Backgrounds: The NuRD (Nucleosome Remodeling and Deacetylation) complex is a repressive complex in gene transcription by modulating chromatin accessibility of target genes to transcription factors and RNA polymerase II. Although individual subunits of the complex have been implicated in many other cancer types, the complex's role in human hepatocellular carcinoma (HCC) is not fully understood. More importantly, the NuRD complex has not yet been investigated as a whole in cancers. Methods: We analyzed the expression of the NuRD complex in HCC and evaluated the prognostic value of NuRD complex expression in HCC using the RNA-seq data obtained from the TCGA project. We examined the effect of CHD4 knockdown on HCC cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition, colony-forming ability, and on complement gene expression. We also performed bioinformatic analyses to investigate the correlation between the NuRD complex expression and immune infiltration. Results: We found that nine subunits, out of 14 subunits of the NuRD complex examined, were significantly overexpressed in HCC, and their expression levels were positively correlated with cancer progression. More importantly, our data also demonstrated that these subunits tended to be overexpressed as a whole in HCC. Subsequent studies demonstrated that knockdown of CHD4 in HCC cells inhibits cell proliferation, migration, invasion, and colony-forming ability and promotes apoptosis of HCC cells, indicating that the CHD4/NuRD complex plays oncogenic roles in HCC. Further analysis revealed that the CHD4/NuRD complex regulates complement gene expression in HCC. Intriguingly, we found that the CHD4/NuRD complex expression was inversely correlated with CD8 T cell infiltration in HCC. Conclusions: Our data demonstrate that the CHD4/NuRD complex plays an oncogenic role in human HCC and regulates complement gene expression in HCC cells. The results of inverse correlation between the CHD4/NuRD complex and CD8 T cell and DC cell infiltration in HCC suggest that the CHD4/NuRD complex not only plays direct regulatory roles in HCC cells, but also has an impact on the immune microenvironment of HCC.

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Section: Discussionmentioning

confidence: 80%

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma

et al. 2020

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“… 39 , 105 Interestingly, the combination of belinostat with ICIs increased their efficacy in an experimental model of HCC. 149 Resminostat, an oral pan-HDACi, was tested in patients with advanced HCC who had previously progressed on sorafenib. The combined administration of resminostat with sorafenib showed clinical efficacy, indicating that this HDACi may restore sensitivity to sorafenib.…”

Section: Targeting Epigenetic Mechanisms In Hccmentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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“…Recently, more and more patients received ICIs combined with surgical resection, chemotherapy, radiotherapy, Tyrosine kinase inhibitors (TKIs), Transarterial chemoembolization (TACE) and others cytotoxic agents or ICIs and acquired acceptable outcomes. [ 10 – 12 ]…”

Section: Introductionmentioning

confidence: 99%

Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors

Ye²

2020

Medicine

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Hepatocellular carcinoma (HCC) is one of the most common neoplasms encountered, and its incidence is increasing worldwide. In this study, we explored the characteristics of gut microbiota in patients with primary hepatocellular carcinoma in advanced stage who received immune checkpoint inhibitors (ICIs) based on a large population with hepatitis B virus infection. An initial cohort of 65 patients with metastatic melanoma were included in this study. All patients were treated with ICIs at Fujian provincial geriatric hospital between August 2016 and June 2018. The 16S rDNA V4 region was amplified by Polymerase chain reaction and sequenced on the MiSeq platform. We found that the diversities of the gut microbiota in HCC who received ICIs were obviously increased. Negative feedback, which is controlled by interplay between microbial metabolic activities and host pathways, is thought to promote high bacterial diversity. We focused on the Faecalibacterium genus in response group, and Bacteroidales order in non-response group, and stratified patients into high versus low categories based on the median relative abundance of these taxa in the gut microbiome. Patients with high Faecalibacterium abundance had a significantly prolonged PFS versus those with a low abundance. Conversely, patients with a high abundance of Bacteroidales had a shortened progressive free survival compared to those with a low abundance. In summary, the present study examined the oral and gut microbiome of HCC patients undergoing immune checkpoint inhibitors immunotherapy. Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus non-responders.

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Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model

Cited by 107 publications

References 58 publications

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors

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