Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer

Noel E Donlon; Maria Davern; Andrew Sheppard; Fiona O'Connell; Brendan Moran; Timothy S Nugent; Aisling Heeran; James J Phelan; Anshul Bhardwaj; Christine Butler; Narayanasamy Ravi; Claire L Donohoe; Niamh Lynam-Lennon; Stephen Maher; John V Reynolds; Joanne Lysaght

doi:10.4251/wjgo.v15.i8.1349

Potential of damage associated molecular patterns in synergising radiation and the immune response in oesophageal cancer

World J Gastrointest Oncol. 2023 Aug 15;15(8):1349-1365. doi: 10.4251/wjgo.v15.i8.1349.

Authors

Noel E Donlon¹, Maria Davern², Andrew Sheppard², Fiona O'Connell², Brendan Moran², Timothy S Nugent², Aisling Heeran², James J Phelan², Anshul Bhardwaj², Christine Butler², Narayanasamy Ravi², Claire L Donohoe², Niamh Lynam-Lennon², Stephen Maher², John V Reynolds², Joanne Lysaght²

Affiliations

¹ Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St James's Cancer Institute, Trinity College Dublin, St James's Hospital, Dublin D08, Ireland. donlonn@tcd.ie.
² Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St James's Cancer Institute, Trinity College Dublin, St James's Hospital, Dublin D08, Ireland.

Abstract

Background: There is an intimate crosstalk between cancer formation, dissemination, treatment response and the host immune system, with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments. However, inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive. The release of damage associated molecular patterns (DAMPs) is indicative of immunogenic cell death and propagation of established immune responses. However, there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma (OAC) or by immune cells themselves.

Aim: To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer.

Methods: We investigated the levels of immunogenic cell death-associated DAMPs, calreticulin (CRT) and HMGB1 using an OAC isogenic model of radioresistance. DAMP expression was also assessed directly using ex vivo cancer patient T cells (n = 10) and within tumour biopsies (n = 9) both pre and post-treatment with clinically relevant chemo(radio)therapeutics.

Results: Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro. Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo(radio)therapy, which was significantly higher in tumour tissue compared with peripheral blood. Patients with high expression of HMGB1 had a significantly better tumour regression grade (TRG 1-2) compared to low expressors.

Conclusion: In conclusion, OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors, which correlated with tumour regression grade and lymphatic invasion. It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease.

Keywords: Calreticulin; Damage associated molecular patterns; HMGB1; Oesophageal adenocarcinoma; Radiation; T cells.