title: Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In non-small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8(+) tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8(+) TIL density as an immunoscore in NSCLC.
  
  
  METHODS
  The prognostic impact of stromal CD8(+) TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts.
  
  
  RESULTS
  Stromal CD8(+) TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8(+) TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8(+) TIL density and pStage were independent prognostic variables.
  
  
  CONCLUSIONS
  Stromal CD8(+) TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore.
authors: Department of Oncology, University Hospital of North Norway, Tromso, Norway. Institute of Clinical Medicine, The Arctic University of Norway, Tromso, Norway. tom.donnem@uit.no.
authors: Tom
authors: T
authors: Donnem
authors: Institute of Clinical Medicine, The Arctic University of Norway, Tromso, Norway.
authors: Sigurd M
authors: SM
authors: Hald
authors: Department of Oncology, University Hospital of North Norway, Tromso, Norway. Institute of Clinical Medicine, The Arctic University of Norway, Tromso, Norway.
authors: Erna-Elise
authors: EE
authors: Paulsen
authors: Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway. Institute of Medical Biology, The Arctic University of Norway, Tromso, Norway.
authors: Elin
authors: E
authors: Richardsen
authors: Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway. Institute of Medical Biology, The Arctic University of Norway, Tromso, Norway.
authors: Samer
authors: S
authors: Al-Saad
authors: Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors: Thomas K
authors: TK
authors: Kilvaer
authors: Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Odd Terje
authors: OT
authors: Brustugun
authors: Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Aslaug
authors: A
authors: Helland
authors: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Marius
authors: M
authors: Lund-Iversen
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark. Department of Oncology, Odense University Hospital, Odense, Denmark. Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors: Mette
authors: M
authors: Poehl
authors: Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. Department of Pathology, Odense University Hospital, Odense, Denmark.
authors: Karen Ege
authors: KE
authors: Olsen
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors: Henrik J
authors: HJ
authors: Ditzel
authors: Department of Oncology, Odense University Hospital, Odense, Denmark. Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors: Olfred
authors: O
authors: Hansen
authors: Department of Pathology, Nordland Hospital, Bodo, Norway.
authors: Khalid
authors: K
authors: Al-Shibli
authors: Institute of Medical Biology, The Arctic University of Norway, Tromso, Norway. Department of Pharmacy, The Arctic University of Tromso, Tromso, Norway.
authors: Yury
authors: Y
authors: Kiselev
authors: Department of Community Medicine, The Artic University of Tromso, Tromso, Norway.
authors: Torkjel M
authors: TM
authors: Sandanger
authors: Department of Oncology, University Hospital of North Norway, Tromso, Norway.
authors: Sigve
authors: S
authors: Andersen
authors: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Francesco
authors: F
authors: Pezzella
authors: Department of Oncology, University Hospital of North Norway, Tromso, Norway. Institute of Clinical Medicine, The Arctic University of Norway, Tromso, Norway.
authors: Roy M
authors: RM
authors: Bremnes
authors: Department of Clinical Pathology, University Hospital of North Norway, Tromso, Norway. Institute of Medical Biology, The Arctic University of Norway, Tromso, Norway.
authors: Lill-Tove
authors: LT
authors: Busund
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D002452:Cell Count; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D017154:Stromal Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor