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

Abstract

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.

Inhibition of histone deacetylases attenuates tumor progression and improves immunotherapy in breast cancer

“…Dacinostat (LAQ-824) has been observed to tackle cancer chemoresistance in multiple myeloma ad acute myeloid leukemia ( 99 ). One study demonstrated that dacinostat and givinostat can restore the activity of cytotoxic T lymphocytes in in pancreatic cancer cells ( 100 ). NVP-LAQ824 attenuated tumor growth and angiogenesis and enhanced VEGFR inhibitor PTK787/ZK222584-mediated inhibition of angiogenesis via upregulation of p21 and downregulation of angioprotein-2, Tie-2, VEGF, HIF-1α, and survivin ( 101 ).…”

“…Givinostat (ITF2357) increased cell death and reduced cell proliferation in urothelial carcinoma cells and acute lymphocytic leukemia ( 113 , 114 ). Givinostat enhanced CTL sensitivity in pancreatic cancer cells ( 100 ). In addition, givinostat reduced cancer stemness and reversed transformed phenotype in glioblastoma ( 115 , 116 ).…”

Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death?

“…The activation of PARP1, a DNA damage-repairing enzyme, occurs because of DNA damage. PARP1 overactivity can also impair mitochondrial OXPHOS, increase ROS production, and increase ATP depletion, promoting necroptosis in PDAC [140][141][142][143][144]. Furthermore, ROS are also involved in PDAC cellular migration under the influence of the oncogenic KRAS mutation through the CCL15/ROS axis [145].…”

Vitamin E in the management of pancreatic cancer: A scoping review

“…However, pancreatic cancer eventually develops chemoresistance towards these clinically used agents. Many combination agents[ 7 , 18 , 19 ] and novel drug delivery methods[ 20 - 22 ] are currently under investigation in hope that a safe and effective treatment for pancreatic cancer patients can be found.…”