title: The tumor area occupied by Tbet+ cells in deeply invading cervical cancer predicts clinical outcome.
abstract: BACKGROUND
  Deep invasion of the normal surrounding tissue by primary cervical cancers is a prognostic parameter for postoperative radiotherapy and relatively worse survival. However, patients with tumor-specific immunity in the blood at the time of surgery displayed a much better disease free survival. Here we analyzed if this was due to a more tumor-rejecting immune population in the tumor.
  
  
  METHODS
  Tumor sections from a group of 58 patients with deep normal tissue-invading cervical tumors were stained for the presence of immune cells (CD45), IFNγ-producing cells (Tbet) and regulatory T cells (Foxp3) by immunohistochemistry. The slides were scanned and both the tumor area and the infiltration of the differently stained immune cells were objectively quantified using computer software.
  
  
  RESULTS
  We found that an increased percentage of tumor occupied by CD45+ cells was strongly associated with an enhanced tumor-infiltration by Tbet+ cells and Foxp3+ cells. Furthermore, the area occupied by CD45+ immune cells, Tbet+ cells but not Foxp3+ cells within the tumor were, in addition to the lymph node status of patients, associated with a longer disease free survival and disease specific survival. Moreover, interaction analyses between these immune parameters and lymph node status indicated an independent prognostic effect of tumor infiltrating Tbet+ cells. This was confirmed in a multivariate Cox analysis.
  
  
  CONCLUSIONS
  The area occupied by a preferentially type I oriented CD45+ cell infiltrate forms an independent prognostic factor for recurrence-free and disease-specific survival on top of the patient's lymph node status.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. A.Gorter@lumc.nl.
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. F.A.Prins@lumc.nl.
authors.forename: Frans
authors.initials: F
authors.lastname: Prins
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. M.van_Diepen@lumc.nl.
authors.forename: Merel
authors.initials: M
authors.lastname: van Diepen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. B.S.Punt@lumc.nl.
authors.forename: Simone
authors.initials: S
authors.lastname: Punt
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. shvdburg@lumc.nl.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D030361:Papillomavirus Infections / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000473:pathology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human