Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers

// Marta Uso 1,2,* , Eloisa Jantus-Lewintre 2,3,* , Roy M. Bremnes 4,5 , Silvia Calabuig 2,6 , Ana Blasco 7 , Enrique Pastor 8 , Irene Borreda 9 , Sonia Molina-Pinelo 10 , Luis Paz-Ares 10,11 , Ricardo Guijarro 8 , Miguel Martorell 12 , Jeronimo Forteza 9 , Carlos Camps 1,2,7 and Rafael Sirera 3 1 Department of Medicine, Universitat de Valencia, Valencia, Spain 2 Molecular Oncology Laboratory, Fundacion Investigacion, Hospital General Universitario de Valencia, Valencia, Spain 3 Department of Biotechnology, Universitat Politecnica de Valencia, Valencia, Spain 4 Department of Oncology, University Hospital of North Norway, Tromso, Norway 5 Department of Clinical Medicine, The Arctic University of Norway, Tromso, Norway 6 Department of Pathology, Universitat de Valencia, Valencia, Spain 7 Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain 8 Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain 9 Instituto Valenciano de Patologia, Universidad Catolica de Valencia, Unidad Mixta de Patologia Molecular Centro de Investigacion Principe Felipe (CIPF)-Universidad Catolica de Valencia (UCV), Valencia, Spain 10 Medical Oncology Department, Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain 11 Universidad Complutense de Madrid, Madrid, Spain 12 Department of Pathology, Hospital General Universitario de Valencia, Valencia, Spain * These authros have contributed equally to this work Correspondence to: Rafael Sirera, email: // Carlos Camps, email: // Keywords :NSCLC, prognostic, immune-biomarker, tumor stroma, tumor compartment Received : March 14, 2016 Accepted : July 15, 2016 Published : July 24, 2016 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.