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oai:figshare.com:article/32805593 2026-10-01T16:14:47Z portal_1172 item_type_8 month_year_10_2026

Investigating DNA damage driven immune response in oesophageal adenocarcinoma (OAC) Susie Kennedy (24292787) PUREID: 681747272 oesophageal adenocarcinoma DNA damage immune response immunotherapy chemotherapy Our group previously identified a subgroup of oesophageal adenocarcinoma (OAC) patients with DNA repair deficiency who show improved responses to neoadjuvant chemotherapy using the DNA Damage Immune Response (DDIR) gene expression signature. DDIR positivity is associated with an inflamed tumour microenvironment, including increased lymphocyte infiltration and immune checkpoint expression, features previously identified to be predictive of response to immune checkpoint inhibition (ICI). However, most OAC tumours are DDIR-negative and display an immune “cold” phenotype, making them less likely to respond to ICI. In other cancers, DNA-damaging chemotherapy can activate the DDIR signature via the cGAS-STING pathway, increasing immune infiltration. We therefore investigated whether specific chemotherapy agents could similarly prime OAC tumours to enhance ICI response. <br><br>To identify optimal agents, we used RT-qPCR to assess DDIR-related gene activation in two OAC cell lines following DNA-damaging chemotherapy. The role of the cGAS-STING pathway was examined using siRNA knockdown and CRISPR knockout models. Immunofluorescence quantified micronuclei formation after treatment, including in knockout cells. Anti-tumour effects of chemotherapy with or without ICI were evaluated using a chorioallantoic membrane model, and immune infiltration was assessed. Finally, immune infiltration was analysed in patient samples before and after chemotherapy. <br><br>Epirubicin induced the strongest upregulation of DDIR-related genes, followed by doxorubicin. This activation was reduced in cGAS/STING-deficient models, confirming pathway dependence. Epirubicin also induced micronuclei formation, which occurred independently of cGAS/STING, suggesting it precedes pathway activation. In vivo, epirubicin combined with ICI reduced tumour growth and increased immune infiltration. Patient samples similarly showed increased immune infiltration after epirubicin-containing treatment. <br><br>Overall, epirubicin activates DDIR via the cGAS-STING pathway and enhances anti-tumour immunity with ICI, supporting its use to improve responses in OAC.<br><br><i>Thesis is embargoed until 31 July 2028.</i> 2026-10-01T16:14:47Z Text Thesis 10.17034/32805593.v1 https://figshare.com/articles/thesis/Investigating_DNA_damage_driven_immune_response_in_oesophageal_adenocarcinoma_OAC_/32805593 All Rights Reserved Open Access after 2028-07-31