title: Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: Comparison with tumor-infiltrating T cells and the status of oncogenic drivers.
abstract: OBJECTIVE
  Programmed cell death-1 (PD-1)/programmed cell death-ligand-1 (PD-L1) pathway-targeted immunotherapy has beneficial therapeutic effects in pulmonary squamous cell carcinoma (SqCC) patients. However, the expression patterns of PD-1 and PD-1 ligands (PD-Ls) in pulmonary SqCC remain unclear. Moreover, the association between the PD-1/PD-Ls pathway and the status of oncogenic drivers in pulmonary SqCC is unknown.
  
  
  METHODS
  PD-L1 and PD-L2 expression in tumor cells and the numbers of PD-1(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) were examined in 331 resected SqCC tumors along with matched lymph node metastases from 77 cases using immunohistochemistry. EGFR and FGFR1 and MET expression and genetic status were also examined.
  
  
  RESULTS
  PD-L1 and PD-L2 expression was detected in 26.9% and 23.9% of the pulmonary SqCC samples, respectively. PD-L1 and PD-L2 expression was maintained or increased in the metastatic lymph node tumors in 81.1% and 93.5% of the 77 cases, respectively. The numbers of PD-1(+) and CD8(+) TILs were significantly positively correlated (P<0.001). Cases displaying high PD-L1 expression exhibited consistently high CD8(+) T cell infiltration (P<0.001), even in subgroup analyses according to age, smoking status, tumor size, lymph node metastasis, stage, and the EGFR, MET and FGFR1 status. Moreover, MET expression in the tumors was significantly correlated with high PD-L2 expression and increased PD-1(+) TILs (P=0.001 for both). Increased numbers of CD8(+) or PD-1(+) TILs were significantly associated with prolonged disease-free survival of these patients, whereas PD-L1 and PD-L2 expression had no significant prognostic implications.
  
  
  CONCLUSIONS
  PD-L1 and PD-L2 expression in pulmonary SqCC is associated with an increased number of CD8(+) TILs and increased MET expression, which might provide therapeutic insight into targeting the PD-1/PD-Ls pathway in pulmonary SqCC.
authors: Department of Pathology, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors: Moon-Young
authors: MY
authors: Kim
authors: Department of Pathology, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Jaemoon
authors: J
authors: Koh
authors: Department of Pathology, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Sehui
authors: S
authors: Kim
authors: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors: Heounjeong
authors: H
authors: Go
authors: Department of Pathology, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea. Electronic address: junarplus@chol.com.
authors: Yoon Kyung
authors: YK
authors: Jeon
authors: Department of Pathology, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea. Electronic address: doohyun@snu.ac.kr.
authors: Doo Hyun
authors: DH
authors: Chung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism*; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: CD274; Immunotherapy; MET; Programmed cell death 1; Programmed cell death 1 ligand 2; Squamous cell carcinoma of the lung