title: Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma.
abstract: OBJECTIVE
  Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma.
  
  
  METHODS
  PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset.
  
  
  RESULTS
  PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively).
  
  
  CONCLUSIONS
  Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity.
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Catarina Alisa
authors.initials: CA
authors.lastname: Kunze
authors.affiliation: Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.affiliation: Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|VM Scope GmbH, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wienert
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Lindner
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bockmayr
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Tumorbank Ovarian Cancer Network, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Braicu
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
mesh_terms: D060890:B7-H1 Antigen / Q000032:analysis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D030541:Databases, Genetic; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D046888:Tissue Array Analysis
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger
keywords: PD-1; PD-L1; high grade serous carcinoma; ovarian; tumor-infiltrating lymphocytes