Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

Sim, Wynne; Lim, Wei‐Meng; Hii, Ling‐Wei; Leong, Chee‐Onn; Mai, Chun‐Wai

doi:10.3748/wjg.v28.i18.1934

Cited by 13 publications

(21 citation statements)

References 74 publications

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“…HDACs are epigenetic enzymes that remove acetyl groups from the lysine residues in histones. Deacetylation of histones promote chromatin condensation, leading to transcriptional repression [ 58 ]. To date, a total of 18 HDAC enzymes have been identified in humans and classified into five phylogenetic classes based on homology to yeast deacetylases: class I (HDAC-1, -2, -3, and -8), class IIa (HDAC4, -5, -7, and -9), class IIb (HDAC6 and -10), class III (sirtuins/SIRT1-7), and class IV (HDAC11) [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Deacetylation of histones promote chromatin condensation, leading to transcriptional repression [ 58 ]. To date, a total of 18 HDAC enzymes have been identified in humans and classified into five phylogenetic classes based on homology to yeast deacetylases: class I (HDAC-1, -2, -3, and -8), class IIa (HDAC4, -5, -7, and -9), class IIb (HDAC6 and -10), class III (sirtuins/SIRT1-7), and class IV (HDAC11) [ 58 ]. Significant evidence has emerged that the epigenetic dysregulation of immune-related genes/pathways play a crucial role in the development of immune evasion in cancer and resistance to immunotherapies [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, a total of 18 HDAC enzymes have been identified in humans and classified into five phylogenetic classes based on homology to yeast deacetylases: class I (HDAC-1, -2, -3, and -8), class IIa (HDAC4, -5, -7, and -9), class IIb (HDAC6 and -10), class III (sirtuins/SIRT1-7), and class IV (HDAC11) [ 58 ]. Significant evidence has emerged that the epigenetic dysregulation of immune-related genes/pathways play a crucial role in the development of immune evasion in cancer and resistance to immunotherapies [ 58 ]. Moreover, expression of the HDACs is frequently deregulated in various cancers, including breast cancer [ 59 ], lung cancer [ 60 ], and PDAC [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…The increase of both histone and acetyl histone proteins clearly indicates a possible disruption of a balance between HAT and HDAC. Aberrant histone acetylation due to the imbalance activity of HATs and HDAC activity within the tumour cells may cause the transcriptional repression of tumour suppressor genes and impair the activation of antitumour immunity, promote immune escape and drug resistance, and ultimately contribute to tumour development and progression [ 58 ]. Notably, HDAC activity could be due to non-histone proteins pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, HDAC activity could be due to non-histone proteins pathways. HDAC can also regulate other transcription factors such as STAT3, TP53, RB, and NF-kB [ 6 , 58 ]. The high acetyl histone levels among CTLr PDAC may also be independent of HAT or HDAC activity.…”

Section: Discussionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Looi

Gan

Sim

et al. 2022

Cancers

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Despite medical advancements, the prognosis of pancreatic ductal adenocarcinoma (PDAC) has not improved significantly over the past 50 years. By utilising the large-scale genomic datasets available from the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we studied the immunophenotype of PDAC in silico and identified that tumours with high cytotoxic T lymphocytes (CTL) killing activity were associated with favourable clinical outcomes. Using the STRING protein–protein interaction network analysis, the identified differentially expressed genes with low CTL killing activity were associated with TWIST/IL-6R, HDAC5, and EOMES signalling. Following Connectivity Map analysis, we identified 44 small molecules that could restore CTL sensitivity in the PDAC cells. Further high-throughput chemical library screening identified 133 inhibitors that effectively target both parental and CTL-resistant PDAC cells in vitro. Since CTL-resistant PDAC had a higher expression of histone proteins and its acetylated proteins compared to its parental cells, we further investigated the impact of histone deacetylase inhibitors (HDACi) on CTL-mediated cytotoxicity in PDAC cells in vitro, namely SW1990 and BxPC3. Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Looi

Gan

Sim

et al. 2022

Cancers

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Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

Tang,

Cui,

Liu

et al. 2024

Cancer Communications

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Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy‐insensitive tumors into immunotherapy‐sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

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Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges

Xu,

Tian,

et al. 2024

MedComm – Oncology

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As the largest microecosystem in the human body, gut microbes (GMs) and their metabolites play an important role in regulating human health. In recent years, immune checkpoint therapy (ICT) combined with antiangiogenic agents is an emerging combination therapy for cancer. There is growing evidence that GMs can affect the effectiveness of drugs to treat cancer. GMs not only regulate angiogenesis in the tumor microenvironment, but also influence the efficacy of immune checkpoint inhibitors. Many studies show that Bifidobacterium can upregulate the anticancer function of immune checkpoint blockers. In addition, GMs have been found to be involved in the formation of blood vessels and other developmental processes. Clinically, GMs are believed to play a key role in patients receiving antiangiogenic therapy and ICT. In this perspective, we provide an overview of the composition and function of the gut microbiome, and discuss the role of the GMs against the conditioning of angiogenic therapy and ICT. We also summarize new approaches and clinical translational trials using GMs for cancer therapy, and present opportunities and challenges for targeting GMs for cancer therapy in the future.

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Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

Cited by 13 publications

References 74 publications

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges

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