title: High ratio of programmed cell death protein 1 (PD-1)(+)/CD8(+) tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy.
abstract: OBJECTIVE
  This study investigated the prognostic role of PD-L1 expression, PD-1(+) tumor-infiltrating lymphocytes (TILs), and the ratio of PD-1(+)/CD8(+) TILs in extrahepatic bile duct (EHBD) cancer.
  
  
  METHODS
  We analyzed 83 patients with EHBD cancer who underwent curative surgery plus fluoropyrimidine-based chemoradiotherapy (CRT). Expressions of PD-L1, PD-1, and CD8 were assessed by immunohistochemistry.
  
  
  RESULTS
  Fifty-six (68%) patients were PD-L1-positive, and its lower expression level was associated with hilar tumor location (P=0.044). A higher ratio of PD-1(+)/CD8(+) TILs was associated with poorer overall survival (OS) (P=0.032), relapse-free survival (RFS) (P=0.024), and distant metastasis-free survival (DMFS) (P=0.039) in Kaplan-Meier analyses, but survival differences were not observed according to the PD-L1 expression level. With Cox proportional hazards models, the ratio of PD-1(+)/CD8(+) TILs was the independent prognostic factor in OS (HR 2.47, 95% CI 1.04-5.86), RFS (HR 2.41, 95% CI 1.08-5.41), and DMFS (HR 2.67, 95% CI 1.00-7.11) after adjusting for other significant clinicopathologic variables.
  
  
  CONCLUSIONS
  A strong survival impact of the ratio of PD-1(+)/CD8(+) TILs was observed in EHBD cancer. In the poor prognostic subgroup, the blockade of the immune checkpoint in combination with conventional multimodality treatment needs to be considered.
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea. Electronic address: yujindw@gmail.com.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Lim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Republic of Korea. Electronic address: tarda@naver.com.
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Koh
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea. Electronic address: kyubokim@snu.ac.kr.
authors.forename: Kyubo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Republic of Korea. Electronic address: ekchie93@snu.ac.kr.
authors.forename: Eui Kyu
authors.initials: EK
authors.lastname: Chie
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea. Electronic address: merdeglas@hanmail.net.
authors.forename: BoKyong
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Republic of Korea. Electronic address: kblee@snuh.org.
authors.forename: Kyoung Bun
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Republic of Korea. Electronic address: jangjy4@gmail.com.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Republic of Korea. Electronic address: sunkim@snu.ac.kr.
authors.forename: Sun-Whe
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea. Electronic address: ohdoyoun@snu.ac.kr.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Republic of Korea. Electronic address: bangyj@snu.ac.kr.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Department of Radiation Oncology, Seoul National University College of Medicine, Republic of Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Republic of Korea. Electronic address: swha@snu.ac.kr.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Ha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D017734:Bile Ducts, Extrahepatic; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D059186:Chemoradiotherapy, Adjuvant; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D016016:Proportional Hazards Models
chemical_list: D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: Adjuvant chemoradiotherapy; Bile duct neoplasms; CD8; Programmed cell death 1 ligand 1 protein; Programmed cell death 1 protein