title: Program Death 1 Immune Checkpoint and Tumor Microenvironment: Implications for Patients With Intrahepatic Cholangiocarcinoma.
abstract: Program death 1 (PD-1) and its ligand (PD-L1) have been identified as potential therapeutic targets for solid and hematologic malignancies. The current study aimed to assess PD-L1 expression in intrahepatic cholangiocarcinoma (ICC) and relate clinical outcomes to its expression.
  
  
  
  Formalin-fixed, paraffin-embedded tumor specimens were obtained for patients undergoing surgery at Johns Hopkins Hospital between 1991 and 2011. Immunohistochemistry was used to assess PD-L1 expression in tumor-associated macrophages (TAMs) and within the tumor front (TF).
  
  
  
  Of 54 tumor samples analyzed, 34 stained positive for PD-L1 expression on TAMs (TAMs+), and 39 stained positive for PD-L1 expression on cells within the tumor front (TF+). The TF+ patients were less likely to present with metastatic lymph nodes (N1 patients: 26.7 vs 7.7 %; p = 0.011), whereas all tumors with intrahepatic metastasis failed to demonstrate staining for PD-L1 around the tumor front (p = 0.020). Patients with tumors shown to be TAMs+ were less likely to present with multiple lesions (35.0 vs 8.8 %; p = 0.017). Patients with tumors exhibiting PD-L1 expression around the tumor front demonstrated a worse overall survival than TF patients (p = 0.008). Multivariable analysis showed that patients with tumors staining for PD-L1 in the tumor front had a 59.5 % reduced survival (TF- vs TF+: time ratio, 0.405; 95 % confidence interval, 0.215-0.761; p = 0.005).
  
  
  
  Expression of PD-L1 was noted among a majority of patients, and PD-L1 expression within the tumor front was associated with a 60 % decreased survival. Future clinical trials are necessary to assess the safety and efficacy of anti-PD-L1 therapies among patients with ICC.
authors.affiliation: Department of Surgery, John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Faiz
authors.initials: F
authors.lastname: Gani
authors.affiliation: Department of Surgery, John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Nagarajan
authors.affiliation: Department of Surgery, John Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yuhree
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Luan
authors.affiliation: Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, AmeriPath Indiana, Indianapolis, IN, USA.
authors.forename: Feriyl
authors.initials: F
authors.lastname: Bhaijjee
authors.affiliation: Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rander54@jhmi.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Surgery, John Hopkins University School of Medicine, Baltimore, MD, USA. tpawlik1@jhmi.edu.|Division of Surgical Oncology, Department of Surgery, John L. Cameron Professor of Alimentary Tract Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. tpawlik1@jhmi.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Pawlik
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015996:Survival Rate; D059016:Tumor Microenvironment
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor