AB054. SOH21AS148. Novel insights into immune-independent functions of immune checkpoint inhibitors in oesophageal adenocarcinoma—potential implications for overcoming chemoresistance to first-line chemotherapy regimens
Plenary Session

AB054. SOH21AS148. Novel insights into immune-independent functions of immune checkpoint inhibitors in oesophageal adenocarcinoma—potential implications for overcoming chemoresistance to first-line chemotherapy regimens

Maria Davern1, Croi Ellen Buckley1, Claire Fitzgerald2, Aisling Heeran1, Noel Donlon2,3, Andrew Sheppard2,3, Anshul Bhardwaj2,3, John Reynolds2,3, Ravi Narayanasamy2,3, Niamh Lynam-Lennon2,3, Stephen Maher2,3, Joanne Lysaght2,3

1Trinity Translational Medicine Institute, St. James’s Hospital Campus, Dublin, Ireland; 2Department of Physiology, Royal College of Surgeons Ireland, Ireland; 3Department of Surgery, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland

Background: Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumour immunity in oesophageal adenocarcinoma (OAC). However, emerging studies have identified novel immune-independent functions for immune checkpoints (ICs) in other solid tumour-types, whereby IC signalling in gastric cancer cells confers chemoresistance. This study explores immune-independent functions of ICs in OAC and if therapeutic blockade may enhance treatment efficacy.

Methods: OAC cells were screened in vitro and ex vivo for a range of ICs (PD-1, TIGIT, TIM-3, LAG-3, A2aR, PD-L1, PD-L2, CD160) by flow cytometry. The phenotype of OAC cells expressing ICs was also assessed for features of stemness (ALDH, CD54), senescence (β-galactosidase) and invasiveness (vimentin) in the absence and presence of chemotherapy by flow cytometry. Importantly, the effect of ICIs on viability (CCK-8 assay and western blot to assess Bcl-xL), proliferation (BrdU assay), chemo-sensitivity (annexin-V propidium iodide assay), metabolism (seahorse), invasiveness and stemness characteristics (flow cytometry) was assessed in OAC cells.

Results: A subpopulation of stem-like, senescent and vimentin+ cells were enriched for ICs, which was enhanced by FLOT and CROSS. Blockade of PD-1, TIGIT, A2aR, TIM-3 and PD-L1 decreased proliferation, induced apoptosis and enhanced toxicity of FLOT in OAC cells. Blockade of TIGIT decreased pro-survival Bcl-xL factor, induced cell death and promoted a more glycolytic phenotype in OAC cells.

Conclusions: Several novel ICs have been identified as potential targets to enhance chemotherapy efficacy in OAC. Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance for stem-like, senescent and vimentin+ aggressive cancer cell clones. Combination ICIs may be required to enhance efficacy of chemotherapy in OAC patients and warrants further investigation.

Keywords: Immune checkpoints (ICs); chemotherapy; oesophageal cancer; senescence; stem-like cancer cells

Acknowledgments

Funding: None.

Footnote

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-21-ab054
Cite this abstract as: Davern M, Buckley CE, Fitzgerald C, Heeran A, Donlon N, Sheppard A, Bhardwaj A, Reynolds J, Narayanasamy R, Lynam-Lennon N, Maher S, Lysaght J. SOH21AS148. Novel insights into immune-independent functions of immune checkpoint inhibitors in oesophageal adenocarcinoma—potential implications for overcoming chemoresistance to first-line chemotherapy regimens. Mesentery Peritoneum 2021;5:AB054.

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