Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer Antonio Calles, MD, Xiaoyun Liao, MD,

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Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer Antonio Calles, MD, Xiaoyun Liao, MD, PhD, Lynette M. Sholl, MD, Scott J. Rodig, MD, PhD, Gordon J. Freeman, PhD, Mohit Butaney, BS, Christine Lydon, Suzanne E. Dahlberg, PhD, F.Stephen Hodi, MD, Geoffrey R. Oxnard, MD, David M. Jackman, MD, Pasi A. Jänne, MD, PhD Journal of Thoracic Oncology Volume 10, Issue 12, Pages 1726-1735 (December 2015) DOI: 10.1097/JTO.0000000000000687 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Programmed death-ligand 1 (PD-L1), PD-L2, and programmed cell death protein 1 (PD-1) expression in formalin-fixed, paraffin-embedded (FFPE) samples of KRAS-mutant lung cancer. Lung adenocarcinoma specimens showing different PD-L1 and PD-L2 intensities of expression in tumor cells and PD-1 expression in tumor-infiltrating lymphocytes weak; 2+, moderate; 3+, intense). Samples stained with anti-PD-L1 antibody (clone 9A11), anti-PD-L2 (clone 9E5), and anti-PD-1 (clone EH33). Scale bar, 100 μm. Journal of Thoracic Oncology 2015 10, 1726-1735DOI: (10.1097/JTO.0000000000000687) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Programmed death-ligand 1 (PD-L1) expression in KRAS-mutant non–small-cell lung cancer (NSCLC) and association with smoking status. A, PD-L1 expression is detected in current smokers (44%), former smokers (20%), and never smokers (13%); n = 114, p = 0.03. B, Higher intensity of PD-L1 expression (IHC-2+/3+) was more frequently observed in smokers (specially in current smokers), whereas weak or negative expression was more frequent in never smokers. C, More intense PD-L1 expression (immunohistochemistry [IHC]-2+/3+) is associated to more pack-years of smoking (34 pack-years compared with 20 pack-years in the group of patients with PD-L1 IHC-0/1+, p = 0.015); D, PD-L1 expression fades with the age of formalin-fixed, paraffin-embedded (FFPE) tumor blocks, particularly in older than 3 years since specimen collection. Journal of Thoracic Oncology 2015 10, 1726-1735DOI: (10.1097/JTO.0000000000000687) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Heterogeneity of programmed cell death protein (PD)-1, PD-L1, and PD-L2 expression in KRAS-mutant non-small-cell lung cancer (NSCLC). A, Association between absolute number of total tumor-infiltrating lymphocytes (TILs) determined by CD3+ staining and PD-1 activated lymphocytes in tumor specimens (n = 20) (left). Five cases with CD3+ TILs were negative for PD-1 staining; association between PD-L1 and PD-1 expression (middle), and between PD-L2 and PD-1 (right). A trend toward more PD-1 TILs was observed in samples with PD-L1 immunohistochemistry (IHC)-3+ expression. B, Different patterns of expression of PD-1, PD-L1, and PD-L2 observed in KRAS-mutant NSCLC (n = 114), categorized into four different tumor microenvironments. C, Example of a KRAS G12C lung adenocarcinoma with adaptive immune resistance, showing intense PD-L1 expression (IHC-3+), negative PD-L2 expression, and infiltrated by a high number of PD-1-positive TILs surrounding the tumor cells. Some immune cells in the tumor stroma show immunoreactivity to PD-L1 and PD-L2, probably indicating antigen trafficking. Journal of Thoracic Oncology 2015 10, 1726-1735DOI: (10.1097/JTO.0000000000000687) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions