title: PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression.
abstract: BACKGROUND
  PD-L1 (programmed death ligand 1, B7-H1) is a cell surface glycoprotein that can impair T-cell function. PD-L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD-L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder.
  
  
  METHODS
  Using immunohistochemistry, PD-L1 expression was evaluated in a cohort of 280 high-risk UCs of the bladder. PD-L1 was modeled as a predictor of bladder cancer stage using ordinal logistic regression. Other covariates evaluated as potential confounders included age, gender, tumor grade, and lymphocytic infiltration. Further, PD-L1 was evaluated as a potential mechanism of bacillus Calmette-Guerin (BCG) failure in the subset of high-risk nonmuscle-invasive tumors that received this treatment.
  
  
  RESULTS
  PD-L1 expression was observed in 7% of pTa, 16% of pT1, 23% of pT2, 30% of pT3/4, and 45% of carcinoma in situ (CIS) tumors. PD-L1 expression was associated with high-grade tumors (odds ratio [OR] = 2.4, P = .009) and tumor infiltration by mononuclear cells (OR = 5.5, P = .004). We observed that the key determinants of stage progression in this cohort were World Health Organization/International Society of Urologic Pathology (WHO/ISUP) high-grade tumor pathology (OR = 4.77, 95% confidence interval [CI]: 2.73-8.34; P < .001) and PD-L1 expression (OR = 2.20, P = .012). PD-L1 expression was found to be extremely abundant in the BCG-induced bladder granulomata in 11 of 12 patients failing BCG treatment.
  
  
  CONCLUSIONS
  Collectively, these data indicate that tumor PD-L1 may facilitate localized stage-advancement of UC and attenuate responses to BCG immunotherapy by neutralizing T cells that normally guard against cancer invasion from the epithelium into the bladder musculature.
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Brant A
authors.initials: BA
authors.lastname: Inman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sebo
authors.forename: Xavier
authors.initials: X
authors.lastname: Frigola
authors.forename: Haidong
authors.initials: H
authors.lastname: Dong
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bergstralh
authors.forename: Igor
authors.initials: I
authors.lastname: Frank
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Kwon
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis*; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor / Q000032:analysis; D002278:Carcinoma in Situ / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006099:Granuloma / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009367:Neoplasm Staging; D020728:Transurethral Resection of Prostate; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human