title: Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status.
abstract: Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1(+) and CD8(+) tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P < 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P < 0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P =0.054) and expression of EGFR and MET (P < 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (P < 0.001) and ERBB2 (P = 0.013). The numbers of CD8(+) and programmed cell death-1(+) lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (P < 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1(+)/CD8(+) lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Koh
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Heounjeong
authors.initials: H
authors.lastname: Go
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Genetic Epidemiology and Preventive Medicine, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Min
authors.affiliation: Department of Thoracic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Tae
authors.initials: YT
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon Kyung
authors.identifier: http://orcid.org/0000-0001-8466-9681
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.|Ischemic/Hypoxia Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060890:B7-H1 Antigen / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000032:analysis*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor