title: Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer.
abstract: BACKGROUND
  Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients.
  
  
  METHODS
  We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis.
  
  
  RESULTS
  Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21-0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL(high)=96%, HPV-positive/TIL(low)=59%). Survival of HPV-positive/TIL(low) patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a 'training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82).
  
  
  CONCLUSIONS
  Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.
authors.affiliation: 1] Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK [2] Department of Otolaryngology-Head and Neck Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ward
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Thirdborough
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: T
authors.initials: T
authors.lastname: Mellows
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: C
authors.initials: C
authors.lastname: Riley
authors.affiliation: Department of Medical Statistics, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: S
authors.initials: S
authors.lastname: Harris
authors.affiliation: Department of Cellular Pathology, Bart's and The London School of Medicine and Dentistry, Garrod Building, Turner Street, Whitechapel, London E1 2AD, UK.
authors.forename: K
authors.initials: K
authors.lastname: Suchak
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Webb
authors.affiliation: Macmillan Head, Neck and Thyroid Specialist Nurse Team, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: C
authors.initials: C
authors.lastname: Hampton
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: N N
authors.initials: NN
authors.lastname: Patel
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Randall
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Poole NHS Foundation Trust, Longfleet Road, Poole BH15 2JB, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Cox
authors.affiliation: Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: S
authors.initials: S
authors.lastname: Jogai
authors.affiliation: Department of Surgery, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: J
authors.initials: J
authors.lastname: Primrose
authors.affiliation: Department of Cellular Pathology, Bart's and The London School of Medicine and Dentistry, Garrod Building, Turner Street, Whitechapel, London E1 2AD, UK.
authors.forename: K
authors.initials: K
authors.lastname: Piper
authors.affiliation: 1] Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK [2] NIHR Experimental Cancer Medicine Centre Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Ottensmeier
authors.affiliation: 1] Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK [2] Department of Otolaryngology-Head and Neck Surgery, Poole NHS Foundation Trust, Longfleet Road, Poole BH15 2JB, UK [3] NIHR Experimental Cancer Medicine Centre Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: E V
authors.initials: EV
authors.lastname: King
authors.affiliation: 1] Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK [2] Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK [3] NIHR Experimental Cancer Medicine Centre Southampton, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000276:immunology* / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies