Plenary Session
AB073. SOH24AB_228. Immunomodulatory effect of epigenetic modification on T cell phenotype and checkpoint receptor expression in oesophageal adenocarcinoma
Brendan Moran1,2, Andrew Sheppard2, Aoife Kilgallon2, Matthew Davey1, John Reynolds2,3, Joanne Lysaght2, Noel Donlon1
1Royal College of Surgeons in Ireland, Dublin, Ireland;
2Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James’s Cancer Institute, Trinity College Dublin, Dublin, Ireland;
3Department of Upper GI Surgery, St. James’ Hospital, Dublin, Ireland
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.
Keywords: Oesophageal cancer; immunotherapy; histone deacetylase inhibitors (HDACi); tumour microenvironment; immune checkpoint inhibitors (ICIs)
Acknowledgments
Funding: None.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
doi: 10.21037/map-24-ab073
Cite this abstract as: Moran B, Sheppard A, Kilgallon A, Davey M, Reynolds J, Lysaght J, Donlon N. AB073. SOH24AB_228. Immunomodulatory effect of epigenetic modification on T cell phenotype and checkpoint receptor expression in oesophageal adenocarcinoma. Mesentery Peritoneum 2024;8:AB073.
