title: Image Analysis-based Assessment of PD-L1 and Tumor-Associated Immune Cells Density Supports Distinct Intratumoral Microenvironment Groups in Non-small Cell Lung Carcinoma Patients.
abstract: OBJECTIVE
  We investigated the correlation between immunohistochemical PD-L1 expression and tumor-associated immune cells (TAICs) density in non-small cell lung carcinoma (NSCLC) and correlated them with clinicopathologic variables.
  
  
  METHODS
  Tumor tissue specimens from 254 stage I-III NSCLCs [146 adenocarcinomas; 108 squamous cell carcinomas (SCCs)] were examined. PD-L1 expression in malignant cells and macrophages and the density of TAICs expressing CD3, CD4, CD8, CD57, granzyme B, CD45RO, PD-1, FOXP3, and CD68 were evaluated using immunohistochemistry and image analysis.
  
  
  RESULTS
  Malignant cells PD-L1 H-score > 5 was detected in 23% of adenocarcinomas and 31% of SCCs, and no significant differences were detected comparing both histologies; the median H-score in macrophages was significantly higher in SCC than in adenocarcinoma (P < 0.001). In adenocarcinoma, high malignant cells PD-L1 expression and high TAIC density correlated with solid histology, smoking history, and airflow limitation. Multivariate analysis demonstrated that high CD57-positive cell density correlated with better recurrence-free survival (RFS; P = 0.0236; HR, 0.457) and overall survival (OS; P = 0.0261; HR, 0.481) rates for SCC. High CD68-positive cell density in intratumoral compartment correlated with better RFS (P = 0.0436; HR, 0.553) for adenocarcinoma. The combination of low CD4/CD8/C68-positive cell density and PD-L1 H-score >5 in malignant cells identified small subset of adenocarcinomas with worse outcomes (RFS: P = 0.036; HR, 4.299; OS: P = 0.00034; HR, 5.632).
  
  
  CONCLUSIONS
  We detected different PD-L1 expression and TAIC density patterns in NSCLC. Distinct groups of tumor microenvironment correlated with NSCLC clinicopathologic features, including outcome. Clin Cancer Res; 22(24); 6278-89. ©2016 AACR.
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Parra
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heather
authors.initials: H
authors.lastname: Lin
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mino
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge
authors.initials: J
authors.lastname: Blando
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Boris
authors.initials: B
authors.lastname: Sepesi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Annikka
authors.initials: A
authors.lastname: Weissferdt
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Julie
authors.initials: J
authors.lastname: Izzo
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cesar
authors.initials: C
authors.lastname: Moran
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. iiwistuba@mdanderson.org.|Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018959:CD57 Antigens / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D059016:Tumor Microenvironment / Q000502:physiology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D018959:CD57 Antigens; C423236:CD274 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule