title: Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer.
abstract: BACKGROUND
  Clinical responses to immune checkpoint blockade by anti-programmed cell death protein-1 (PD-1)/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) are associated with PD-L1 expression and smoking status. We aimed to determine the expression profile of PD-1 and its ligands, PD-L1 and PD-L2, in both smokers and never smokers patients with KRAS-mutant NSCLC.
  
  
  METHODS
  We retrospectively analyzed the clinical and molecular characteristics of 114 KRAS-mutant NSCLC patients (84 smokers and 30 never smokers) and their clinical tumor samples for the expression of PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC). We used murine monoclonal antibodies anti-PD-L1 (clone 9A11) and anti-PD-L2 (clone 9E5) to examine for tumor cell expression (0, negative; 1, weak; 2, moderate; 3, intense) and anti-PD-1 (clone EH33) for tumor-infiltrating lymphocytes.
  
  
  RESULTS
  PD-L1 expression was detected in 27 of 114 patients (24%; 95% confidence interval [CI], 16-33%) and associated with smoking status (current smokers, 44%; former smokers, 20%; never smokers, 13%; p = 0.03). Higher intensity of PD-L1 expression (IHC-2+/IHC-3+) was more frequently observed in smokers and associated with more pack-years. PD-L2 was positive in 54 of 114 patients (47%; 95% CI, 38-57%) and not related to smoking status. PD-1-positive tumor-infiltrating lymphocytes were present in 77 of 114 tumor specimens tested (68%; 95% CI, 59-77%) including 21 of 27 samples with PD-L1 expression and 39 of 54 samples with PD-L2-positive expression. We found that PD-L1 expression fades with the age of the specimens used for analyses decreasing beyond 3 years (p = 0.016).
  
  
  CONCLUSIONS
  The expression of PD-1 and its ligands PD-L1 and PD-L2 is heterogeneous within KRAS-mutant NSCLC and suggests an inducible expression of PD-L1 by smoking.
authors.affiliation: *Department of Medical Oncology, †Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ‡Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; §Harvard Medical School, Boston, Massachusetts; ‖Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts. ¶Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and #Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Christine
authors.initials: C
authors.lastname: Lydon
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.forename: David M
authors.initials: DM
authors.lastname: Jackman
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000096:biosynthesis* / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012907:Smoking / Q000235:genetics / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C117307:KRAS protein, human; D008024:Ligands; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D016283:Proto-Oncogene Proteins p21(ras)