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      Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-small Cell Lung Cancer (NSCLC)

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          Abstract

          Importance

          Early phase trials with monoclonal antibodies targeting PD-1/PD-L1 have demonstrated durable clinical responses in patients with NSCLC, however, current assays for the prognostic/predictive role of tumor PD-L1 expression are not standardized with respect to either quantity or distribution of expression.

          Objective

          In this study, we demonstrate PD-L1 protein distribution in NSCLC tumors using both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (QIF), and compare results obtained using two different PD-L1 antibodies.

          Design

          PD-L1 was measured using two rabbit monoclonal antibodies (E1L3N and SP142) in 49 NSCLC whole tissue sections and a corresponding tissue microarray with the same 49 cases. Mel624 cells stably transfected with PD-L1, as well as Mel624 parental cells and human term placenta were used as controls and for antibody validation. PD-L1 protein expression in tumor and stroma was assessed using chromogenic IHC and the AQUA ® method of QIF. Tumor-infiltrating lymphocytes (TILs) were scored in hematoxylin/eosin stained slides using current consensus guidelines. The association between PD-L1 protein expression, TILs, and clinico-pathological features were determined.

          Setting

          NSCLC resections were all performed at Yale New Haven Hospital.

          Participants

          NSCLC resection cases from 2011–2012 were collected retrospectively from the Yale Thoracic Oncology Program Tissue Bank in Yale Pathology based on tissue availability.

          Main Outcome Measure

          PD-L1 expression discordance or heterogeneity using DAB and QIF was the main outcome measure selected prior to performing the study.

          Results

          Using chromogenic IHC, both antibodies showed fair to poor concordance. QIF showed that PD-L1 expression using both PD-L1 antibodies was heterogeneous. Using QIF, the scores obtained with E1L3N and SP142 for each tumor were significantly different according to nonparametric-paired test (p <0.001). Assessment of 588 serial section fields of view by QIF showed discordant expression at a frequency of 25%. Expression of PD-L1 using both E1L3N and SP142 was correlated with high TILs (p = 0.007 and p = 0.021).

          Conclusions

          Objective determination of PD-L1 protein levels in NSCLC reveals heterogeneity within tumors and prominent inter-assay variability or discordance. This could be due to different antibody affinities, limited specificity, or distinct target epitopes. Efforts to determine the clinical value of these observations are underway.

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          Author and article information

          Journal
          101652861
          43608
          JAMA Oncol
          JAMA Oncol
          JAMA oncology
          2374-2437
          2374-2445
          2 July 2016
          January 2016
          01 January 2017
          : 2
          : 1
          : 46-54
          Affiliations
          [1 ]Department of Medical Oncology, Yale University School of Medicine, New Haven, CT
          [2 ]Department of Pathology, Yale University School of Medicine, New Haven, CT
          [3 ]Department of Biostatistics, Yale University School of Public Health, New Haven, CT
          [4 ]Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH
          Author notes
          [* ]Corresponding Author: David L. Rimm M.D.-Ph.D., Professor of Pathology, Director, Yale Pathology Tissue Services, Dept. of Pathology, BML 116, Yale University School of Medicine, 310 Cedar St. PO Box 208023, New Haven, CT 06520-8023, Phone: 203-737-4204, FAX: 203-737-5089, david.rimm@ 123456yale.edu
          Article
          PMC4941982 PMC4941982 4941982 nihpa780059
          10.1001/jamaoncol.2015.3638
          4941982
          26562159
          0ae8fa29-740b-4cec-9c67-46c896b7c1f0
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