AB073. SOH24AB_228. Immunomodulatory effect of epigenetic modification on T cell phenotype and checkpoint receptor expression in oesophageal adenocarcinoma

Background: Histone deacetylase inhibitors (HDACi) are immunotherapy agents demonstrating efficacy in malignancies such as T-cell lymphoma and Multiple Myeloma. This study aims to characterise the effects of HDACi on T-cell phenotype and function, both in health and in oesophageal adenocarcinoma (OAC), and identify opportunities for synergism with immune checkpoint inhibitors (ICIs). Methods: Through ex-vivo models, activated T-cells isolated from healthy donors and OAC patients, were treated with four HDACi (panobinostat, romidepsin, tubacin & PCI-34051). T-cell activation, immune checkpoint receptor expression and cytokine production were assessed by flow cytometry, under normal conditions and those of the microenvironment (glucose deprivation, glutamine deprivation and hypoxia). Results: HDACi did not affect activation of T-cells. Under normal conditions in both healthy and OAC T-cells, reductions in PD-1, LAG-3 and TIGIT were noted for all HDACi. Romidepsin significantly reduced TIGIT expression on helper CD4+ T-cells in OAC samples (P<0.01). Tumour microenvironment conditions further enhanced these effects, notably hypoxia. Significant reductions in PD-1, LAG-3 and TIGIT were noted in deprivation states in T-cells treated with panobinostat (P<0.05), romidepsin (P<0.05) and tubacin (P<0.05), while PCI-34051 displayed significant reductions of LAG-3 only (P<0.05). OAC samples demonstrated significantly reduced PD-1 expression at baseline on helper CD4+ T-cells, and significant increases in LAG-3 and TIGIT expression on cytotoxic CD8+ T-cells compared to healthy donors (P<0.05). Conclusions: OAC donor T-cells displayed significant differences in checkpoint expression compared to healthy donors. PCI-34051 maintained checkpoint expression in both healthy and OAC T-cells which could be crucial to understanding the potential of combinational therapeutic strategies with ICIs and epidrugs.