title: Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma.
abstract: BACKGROUND
  Programmed cell death-ligand 1 (PD-L1) is expressed in a subgroup of lung cancer that may benefit from immunotherapy. The interaction between PD-L1 expression and tumour infiltrating lymphocytes (TIL) remains poorly understood. This study investigated the expression of PD-L1 in surgically resected stage I pulmonary squamous cell carcinoma (SqCC) and correlated it with TILs in tumour microenvironments, common driver mutations, and clinical outcomes.
  
  
  METHODS
  One hundred and five patients with surgically resected stage I squamous cell carcinoma were examined. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ≥ 5% of tumour cells were scored as positive for PD-L1 expression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing, while anaplastic lymphoma kinase (ALK), phosphoinositide 3-kinase catalytic alpha (PI3KCA), and fibroblast growth factor receptor 1 (FGFR1) were analysed by immunohistochemistry. The correlations of PD-L1 expression with each subtype of TIL, driver mutations, clinicopathologic parameters, and clinical outcomes were analysed.
  
  
  RESULTS
  There was positive PD-L1 expression in 56.2% (59/105) of patients. PD-L1 expression was not associated with the common clinicopathologic features and mutations of EGFR, KRAS, BRAF, ALK, PI3KCA, and FGFR1. As regards TILs composition, tumour PD-L1 expression was significantly associated with increased tumour epithelial CD8+ T cells and stromal CD4+ T cells. Otherwise, PD-L1 (+) tumour cells were negatively correlated with PD-L1 (+) immune cells within tumour stroma. By multivariate analysis, tumour PD-L1 expression and increased CD4+ T cell infiltrations in the tumour stroma were independent predictors of better overall survival and had a trend of better disease-free survival.
  
  
  CONCLUSIONS
  PD-L1 expression is associated with a favourable immune microenvironment in stage I pulmonary SqCC and correlates with better clinical outcome.
authors.affiliation: Department of Internal Medicine, Taiwan, ROC; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan, ROC.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Surgery, Taiwan, ROC; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan, ROC.
authors.forename: Mong-Wei
authors.initials: MW
authors.lastname: Lin
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7, Chung-Shan South Road, Taipei 10002, Taiwan, ROC; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan, ROC. Electronic address: ntuhylc@gmail.com.
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7, Chung-Shan South Road, Taipei 10002, Taiwan, ROC; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan, ROC.
authors.forename: Chen-Tu
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Taiwan, ROC; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10002, Taiwan, ROC.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D060890:B7-H1 Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Immune microenvironment; Immunotherapy; Programmed cell-death ligand 1; Squamous cell carcinoma