AB053. SOH21AS146. Cooperation between chemotherapy and immunotherapy to enhance anti-tumour T-cell mediated immunity in oesophageal adenocarcinoma: implications for synergistic combination regimens
Plenary Session

AB053. SOH21AS146. Cooperation between chemotherapy and immunotherapy to enhance anti-tumour T-cell mediated immunity in oesophageal adenocarcinoma: implications for synergistic combination regimens

Maria Davern1, Noel Edward Donlon2, Andrew Sheppard3, Fiona O’Connell3, Ross King2, Conall Hayes2, Jenny Moore2, Anshul Bhardwaj2, John Reynolds2, Ravi Narayanasamy2, Stephen Maher2, Melissa Conroy2, Joanne Lysaght2

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

Background: Combining immunostimulatory chemotherapies with immune checkpoint inhibitors (ICIs) to stimulate anti-tumour immunity and prevent immune-exhaustion is an attractive approach to improve outcomes in oesophageal adenocarcinoma (OAC), in particular those with ‘cold and immune-excluded’ tumours.

Methods: Immune checkpoint (IC) expression was profiled on circulating and tumour-infiltrating T-cells perioperatively and correlated with clinical outcomes (n=16). Immunostimulatory and immunoinhibitory effects of chemotherapy regimens (FLOT, CROSS, MAGIC) on T-cells was investigated following 48 h-treatment, via assessment of T-cell activation markers (CD69, ICOS), inhibitory ICs (PD-1, TIGIT, TIM-3, CTLA-4, LAG-3, KLRG-1, PD-L1, PD-L2), T-cell cytokine profiles (TH1-IL-12, IFN-γ, TNF-α, TH2-IL-4, TH17-IL-17A and Treg-IL-10) and T-cell subsets (naïve, effector and central memory) with/without nivolumab and atezolizumab. The effect of chemotherapy regimens on immunogenic cell death (ICD) in OAC cells was also assessed by flow cytometry (calreticulin, HMGB1, MIC-AB, HLA-DR).

Results: ICs were increased on tumour-infiltrating T-cells compared with peripheral T-cells. Pre-treatment, ICs correlated with worse treatment response and advanced tumours (P<0.05). Paradoxically, post-treatment ICs correlated with better treatment response (P<0.05). FLOT and CROSS increased OAC T-cell activation markers (CD69, ICOS), TH1 and TH17 profiles and also increased several ICs. FLOT and CROSS enhanced anti-tumour cytokine production more substantially in healthy donor T-cells versus OAC T-cells. The frequency of effector memory T-cells was increased by FLOT and CROSS and addition of nivolumab/atezolizumab promoted terminal differentiation. FLOT and CROSS induced ICD compared with MAGIC in OAC cells.

Conclusions: A link between chemotherapy and immune-resistance is highlighted. ICIs may enhance the efficacy of immunostimulatory chemotherapies in OAC patients boosting response rates. As FLOT and CROSS induced ICD in OAC cells these regimens may synergise with ICIs in patients.

Keywords: Chemotherapy; immune checkpoints; immunogenic cell death (ICD); immunostimulatory; oesophageal adenocarcinoma (OAC)

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-ab053
Cite this abstract as: Davern M, Donlon NE, Sheppard A, O’Connell F, King R, Hayes C, Moore J, Bhardwaj A, Reynolds J, Narayanasamy R, Maher S, Conroy M, Lysaght J. SOH21AS146. Cooperation between chemotherapy and immunotherapy to enhance anti-tumour T-cell mediated immunity in oesophageal adenocarcinoma: implications for synergistic combination regimens. Mesentery Peritoneum 2021;5:AB053.

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