Abstract:
Pancreatic adenocarcinoma (PDAC) ranks high among the causes of cancer-related mortality. The prognosis of this disease has not improved significantly over the past 50 years despite advancements in imaging techniques, cancer genetics and treatment modalities. Likewise, emerging developments in immunotherapy have yet to bring significant clinical advantage among PDAC patients. Tumour-intrinsic immune evasion mechanisms of PDAC remained poorly understood. By leveraging on the
large-scale genomic datasets reported by the Australia Pancreatic Cancer Project (PACA-AU) and The Cancer Genomic Atlas Project (TCGA-PAAD), we investigated the immunophenotype of PDAC and identified that tumour with low cytotoxic T cell (CTL) killing activity exhibited poorer clinical outcomes as compared to tumour with high CTL killing activity. Integrative transcriptomic analysis identified TWIST1, IL6R, MMP3, and HDAC5 as putative immune modulators, responsible for the tumour-cell
intrinsic immune evasion in pancreatic cancers. Connectivity Map (CMap) analysis identified histone deacetylase (HDAC) inhibitors as potential candidate drugs that could target CTL resistant PDAC. Indeed, in vitro study demonstrated that entinostat and quisinostat enhanced CTL killing of CTL-resistant BxPC3 and SW1990 cells. Overall, these findings suggest the immunomodulatory effects of HDAC inhibitors in pancreatic cancer and warrant further investigation.
