title: Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.
abstract: BACKGROUND
  Programmed cell death 1 (PD-1) receptor triggering by PD ligand 1 (PD-L1) inhibits T cell activation. PD-L1 expression was detected in different malignancies and associated with poor prognosis. Therapeutic antibodies inhibiting PD-1/PD-L1 interaction have been developed.
  
  
  METHODS
  A tissue microarray (n=1491) including healthy colon mucosa and clinically annotated colorectal cancer (CRC) specimens was stained with two PD-L1 specific antibody preparations. Surgically excised CRC specimens were enzymatically digested and analysed for cluster of differentiation 8 (CD8) and PD-1 expression.
  
  
  RESULTS
  Strong PD-L1 expression was observed in 37% of mismatch repair (MMR)-proficient and in 29% of MMR-deficient CRC. In MMR-proficient CRC strong PD-L1 expression correlated with infiltration by CD8(+) lymphocytes (P = 0.0001) which did not express PD-1. In univariate analysis, strong PD-L1 expression in MMR-proficient CRC was significantly associated with early T stage, absence of lymph node metastases, lower tumour grade, absence of vascular invasion and significantly improved survival in training (P = 0.0001) and validation (P = 0.03) sets. A similar trend (P = 0.052) was also detectable in multivariate analysis including age, sex, T stage, N stage, tumour grade, vascular invasion, invasive margin and MMR status. Interestingly, programmed death receptor ligand 1 (PDL-1) and interferon (IFN)-γ gene expression, as detected by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in fresh frozen CRC specimens (n = 42) were found to be significantly associated (r = 0.33, P = 0.03).
  
  
  CONCLUSIONS
  PD-L1 expression is paradoxically associated with improved survival in MMR-proficient CRC.
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland; Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland. Electronic address: rdroeser@uhbs.ch.
authors.forename: Raoul A
authors.initials: RA
authors.lastname: Droeser
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland; Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hirt
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Viehl
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Frey
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland; Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Nebiker
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland.
authors.forename: Xaver
authors.initials: X
authors.lastname: Huber
authors.affiliation: Institute of Pathology, University of Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Institute of Pathology, University of Basel, Switzerland.
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.affiliation: Institute of Pathology, University of Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Surgery, Ospedale Regionale di Lugano, Switzerland.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Rosso
authors.affiliation: Department of Surgery, Kantonsspital Olten, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Zuber
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Manuele Giuseppe
authors.initials: MG
authors.lastname: Muraro
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Amicarella
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cremonesi
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.affiliation: Institute of Pathology, University of Bern, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Institute of Pathology, University of Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Institute of Translational Pharmacology, National Council Research, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.affiliation: Department of Surgery, University Hospital of Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.affiliation: Institute for Surgical Research and Hospital Management ICFS, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
authors.affiliation: Institute of Pathology, University of Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism*; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000401:mortality*; D053843:DNA Mismatch Repair / Q000502:physiology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012004:Rectal Neoplasms / Q000378:metabolism / Q000401:mortality*; D046888:Tissue Array Analysis
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor