Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma

Richard Turkington*, Laura Knight, Jaine Blayney, Maria Secrier, Rosalie Douglas, Eileen Parkes, Eilis Sutton, Leanne Stevenson, Damian McManus, Sophia Halliday, Andrena McCavigan, Gemma Logan, Steven Walker, Christopher Steele, Juliane Perner, Jan Bornscein, Shona MacRae, Ahmad Miremadi, Eamon McCarron, Stephen McQuaidKenneth Arthur, Jacqueline James, Martin Eatock, Robert O'Neill, Fergus Noble, Timothy Underwood, Denis Harkin, Manuel Salto-Tellez, Rebecca C Fitzgerald, Richard Kennedy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
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OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.

DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).

RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).

CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.

Original languageEnglish
Pages (from-to)1918-1927
Number of pages10
Issue number11
Early online date09 Mar 2019
Publication statusEarly online date - 09 Mar 2019

Bibliographical note

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.


  • Adenocarcinoma/immunology
  • Aged
  • Antineoplastic Agents/therapeutic use
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes
  • Chemotherapy, Adjuvant
  • DNA Damage/immunology
  • Disease-Free Survival
  • Esophageal Neoplasms/immunology
  • Esophagectomy
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoadjuvant Therapy
  • Predictive Value of Tests
  • Survival Rate
  • Treatment Outcome

ASJC Scopus subject areas

  • Medicine(all)


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