title: Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma.
abstract: Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10-15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.
  
  
  
  Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.
  
  
  
  Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.
  
  
  
  Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK. f.noble@soton.ac.uk.|Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK. f.noble@soton.ac.uk.
authors.forename: Fergus
authors.initials: F
authors.lastname: Noble
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Mellows
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Leo H
authors.initials: LH
authors.lastname: McCormick Matthews
authors.affiliation: Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Bateman
authors.affiliation: Public Health Sciences and Medical Statistics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Harris
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.|Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Underwood
authors.affiliation: Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Byrne
authors.affiliation: Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Bailey
authors.affiliation: Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Sharland
authors.affiliation: Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Kelly
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.|Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Primrose
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Sahota
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.|Cancer Care, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bateman
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.|Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Somers Cancer Research Building (MP824), Southampton General Hospital, Tremona Road, Southampton, UK.|Cancer Care, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ottensmeier
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D003131:Combined Modality Therapy; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D047368:Tumor Burden
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators
keywords: Cytotoxic T lymphocyte; Immune response; Immunotherapy; Oesophageal adenocarcinoma; Regulatory T cells; Tumour regression