title: Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers.
abstract: The prognosis of non-small cell lung cancer (NSCLC) remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of immune-related markers may provide valuable prognostic information of NSCLC. In 122 formalin-fixed, paraffin-embedded tumor tissue samples from early-stage NSCLC, tumor and tumor-near stromal areas were microdissected and gene expression levels of conventional and regulatory T cell markers were assessed by quantitative polymerase chain reaction. Also, the presence of infiltrating CD4+, CD8+, and FOXP3+ cells in tumor samples was assessed by immunohistochemistry. The relative proportion of conventional and regulatory T cells present in the tumor environment was assessed and found to be key to understand the importance that the immune system analysis has in the prognostics of NSCLC patients. The presence of CD8+ cells in the tumor compartment was associated with better outcome, whereas the presence of FOXP3+ cells was associated with worse overall survival. The negative prognostic value of combined biomarkers, indicating high levels of FOXP3 in the stroma and low levels of CD4 or CD8 in tumors, was observed at mRNA level and was validated by immunohistochemistry.In conclusion, the proportion of T helper and cytotoxic cells vs. regulatory T cells in different locations of the tumor microenvironment have opposite prognostic impacts in resected NSCLC.
authors.affiliation: Department of Medicine, Universitat de València, Valencia, Spain.|Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Usó
authors.affiliation: Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.|Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Jantus-Lewintre
authors.affiliation: Department of Oncology, University Hospital of North Norway, Tromso, Norway.|Department of Clinical Medicine, The Arctic University of Norway, Tromso, Norway.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Bremnes
authors.affiliation: Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.|Department of Pathology, Universitat de València, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig
authors.affiliation: Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Blasco
authors.affiliation: Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Pastor
authors.affiliation: Instituto Valenciano de Patología, Universidad Católica de Valencia, Unidad Mixta de Patología Molecular Centro de Investigación Príncipe Felipe (CIPF)-Universidad Católica de Valencia (UCV), Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Borreda
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Molina-Pinelo
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.|Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Guijarro
authors.affiliation: Department of Pathology, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martorell
authors.affiliation: Instituto Valenciano de Patología, Universidad Católica de Valencia, Unidad Mixta de Patología Molecular Centro de Investigación Príncipe Felipe (CIPF)-Universidad Católica de Valencia (UCV), Valencia, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Forteza
authors.affiliation: Department of Medicine, Universitat de València, Valencia, Spain.|Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.|Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Camps
authors.affiliation: Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sirera
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D015704:CD4 Antigens; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
keywords: NSCLC; immune-biomarker; prognostic; tumor compartment; tumor stroma; Autophagy