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Title: The Immune Microenvironment, Genome-wide Copy Number Aberrations, and Survival in Mesothelioma.
Austin Authors: Thapa, Bibhusal ;Salcedo, Adriana;Lin, Xihui;Walkiewicz, Marzena;Murone, Carmel ;Ameratunga, Malaka;Asadi, Khashayar ;Deb, Siddhartha;Barnett, Stephen A ;Knight, Simon;Mitchell, Paul L R ;Watkins, D Neil;Boutros, Paul C;John, Thomas 
Affiliation: Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada
Department of Pathology, Austin Health, Heidelberg, Victoria, Australia
Department of Medical Oncology, Austin Health, Olivia-Newton John Cancer and Wellness Centre, Heidelberg, Victoria, Australia
Department of Thoracic Surgery, Austin Health, Heidelberg, Victoria, Australia
Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Issue Date: 2017
Date: 2017
Publication information: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2017; 12(5): 850-859
Abstract: Results of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as programmed cell death protein 1 and its ligand programmed death ligand 1 (PD-L1) have not been well characterized in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates, and genome-wide copy number status and correlated them to clinicopathological features. Tissue microarrays were constructed and stained with PD-L1(clone E1L3N [Cell Signaling Technology, Danvers, MA]), cluster of differentiation 4, cluster of differentiation 8, and forkhead box P3 antibodies. PD-L1 positivity was defined as at least 5% membranous staining regardless of intensity, and high PD-L1 positivity was defined as at least 50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations to other variables. Among 329 patients evaluated, PD-L1 positivity was detected in 130 of 311 (41.7%), but high PD-L1 positivity was seen in only 30 of 311 (9.6%). PD-L1 positivity correlated with nonepithelioid histological subtype and increased infiltration with cluster of differentiation 4-positive, cluster of differentiation 8-positive, and forkhead box P3-positive lymphocytes. High PD-L1-positive expression correlated with worse prognosis (hazard ratio = 2.37, 95% confidence interval: 1.57-3.56, p < 0.001) in univariate analysis but not in multivariate analysis. Higher percent genome alteration was associated with epithelioid histological subtype and poorer survival (hazard ratio = 1.59, 95% confidence interval: 1.01-2.5, p = 0.04) but not PD-L1 expression. PD-L1 expression was associated with nonepithelioid MPM, poor clinical outcome, and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression but was associated with poorer survival.
DOI: 10.1016/j.jtho.2017.02.013
ORCID: 0000-0002-8350-2860
Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
PubMed URL: 28257959
PubMed URL:
Type: Journal Article
Subjects: Copy number aberrations
Tumor-infiltrating lymphocytes
Appears in Collections:Journal articles

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