title: PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung.
abstract: PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy for pulmonary adenocarcinoma (pADC). Epithelial-to-mesenchymal transition (EMT) is involved in the progression and immune evasion of cancers. Therefore, we investigated the association between PD-L1 expression and EMT phenotype in pADC. Immunohistochemistry for E-cadherin (epithelial marker), ZEB1, SNAIL, SLUG, vimentin (mesenchymal markers), PD-L1, CD8, and PD-1 was performed on 477 cases of pADC. Cases were classified into epithelial, mesenchymal, epithelial-mesenchymal, and unspecified types based on immunohistochemical results. PD-L1 expression was scored as 0 in 14.0% (n=67), 1 in 26.4% (n=126), 2 in 51.2% (n=244), and 3 in 8.4% (n=40). PD-L1 score was positively correlated with SNAIL and vimentin H scores (P<.001, both). After dichotomizing patients into PD-L1-negative and PD-L1-positive groups, PD-L1 positivity was significantly higher in patients with mesenchymal (71.2%; 84/118) and epithelial-mesenchymal (62.7%; 84/134) phenotypes compared with those with epithelial (50.6%; 44/87) and unspecified (50.0%; 35/70) phenotypes (P=.005). The significant association between PD-L1 expression and EMT phenotype was maintained in EGFR-mutated pADCs. Moreover, cases with EMT phenotype (ie, mesenchymal and epithelial-mesenchymal) were infiltrated by higher numbers of CD8+and PD-1+cells than those with epithelial and unspecified phenotypes in EGFR-mutated pADCs (P=.043 for CD8+cells and P<.001 for PD-l+cells). Particularly, cases with EMT phenotype and PD-L1 expression showed the greatest amount of CD8+and PD-1+cells in EGFR-mutated cases (P=.043 for CD8+cells and P=.005 for PD-1+cells). This study demonstrates that EMT phenotype is related to PD-L1 overexpression in pADC cells and patients with EMT-phenotype pADC may benefit from PD-1/PD-L1-blocking immunotherapy.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Sehui
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Koh
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea.
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Dohee
authors.initials: D
authors.lastname: Kwon
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Heounjeong
authors.initials: H
authors.lastname: Go
authors.affiliation: Department of Pathology, Seoul Metropolitan Government Boramae Hospital, Seoul 07061, Republic of Korea.
authors.forename: Young A
authors.initials: YA
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: junarplus@chol.com.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: doohyun@snu.ac.kr.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D012189:Retrospective Studies; D000071250:Snail Family Transcription Factors / Q000032:analysis; D046888:Tissue Array Analysis; D014746:Vimentin / Q000032:analysis; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000071250:Snail Family Transcription Factors; D014746:Vimentin; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Adenocarcinoma of the lung; Cancer immunotherapy; Epithelial-mesenchymal transition; Immune checkpoint; Programmed cell death 1; Programmed cell death 1 ligand 1