title: Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma.
abstract: BACKGROUND
  Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) pathway negatively regulates T-cell-mediated responses. The prognostic impact of PD-L1 expression needs to be defined in urothelial carcinoma (UC).
  
  
  METHODS
  Formalin-fixed paraffin-embedded tumor samples from 160 patients with UC were retrieved. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). PD-L1 positivity on tumor cell membrane was defined as ≥5% of tumor cell membrane staining. The extent of tumor-infiltrating mononuclear cells (TIMCs) as well as PD-L1 expression on TIMCs was scored from 0 to 4. A score of 2, 3, or 4 was considered PD-L1-positive. Clinico-pathological variables were documented. The Cox regression model was used to assess the association of PD-L1 expression with overall survival (OS) in patients who developed metastases.
  
  
  RESULTS
  TIMCs were present in 143 of the 160 patient samples. Out of 160 samples, 32 (20%) had positive PD-L1 expression in tumor cell membrane. Out of 143 samples with TIMCs, 58 (40%) had positive PD-L1 expression in TIMCs. Smoking history, prior BCG use and chromosome 9 loss did not correlate with PD-L1 expression in either tumor cell membrane or TIMCs. PD-L1 positivity was not different between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy (n = 100), PD-L1 positivity on tumor cell membrane was seen in 14% of patients and did not correlate with OS (P = 0.45). Out of 89 M1 patients who had evaluable PD-L1 on TIMCs, PD-L1 expression was seen in 33% of patients and was significantly associated with longer OS on multivariate analysis (P = 0.0007).
  
  
  CONCLUSIONS
  PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not predictive of OS. However, positive PD-L1 expression in TIMCs was significantly associated with longer survival in those patients who developed metastases.
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Brigham and Women's Hospital, Boston; Medical Oncology Department, Harvard Medical School, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston. Electronic address: joaquim_bellmunt@dfci.harvard.edu.
authors.forename: J
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston.
authors.forename: S A
authors.initials: SA
authors.lastname: Mullane
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston.
authors.forename: L
authors.initials: L
authors.lastname: Werner
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston.
authors.forename: A P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston.
authors.forename: M
authors.initials: M
authors.lastname: Callea
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston.
authors.forename: J J
authors.initials: JJ
authors.lastname: Leow
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Brigham and Women's Hospital, Boston; Medical Oncology Department, Harvard Medical School, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston.
authors.forename: M E
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Brigham and Women's Hospital, Boston; Medical Oncology Department, Harvard Medical School, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston.
authors.forename: T K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Medical Oncology Department, Harvard Medical School, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston; Center for Immuno-oncology, Dana-Farber Cancer Institute, Boston, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Medical Oncology Department, Harvard Medical School, Boston; Medical Oncology Department, Dana-Farber Cancer Institute, Boston.
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston; Medical Oncology Department, Harvard Medical School, Boston; Department of Pathology, Brigham and Women's Hospital, Boston.
authors.forename: S
authors.initials: S
authors.lastname: Signoretti
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000401:mortality* / Q000556:secondary; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011379:Prognosis; D015996:Survival Rate; D014571:Urologic Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: PD-1; PD-L1; immunotherapy; overall survival; prognosis; urothelial carcinoma