PD‐L1 (B7‐H1) expression by urothelial carcinoma of the bladder and BCG‐induced granulomata

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. Cancer 2007. © 2007 American Cancer Society.

The Programmed Death-1 Immune-Suppressive Pathway: Barrier to Antitumor Immunity

“…These latter findings were interpreted as confirming the concept that increased PD-L1 was due to the presence of IFNγ-secreting tumor-reactive TIL. However, studies using the same assessment criteria and anti-PD-L1 antibody, revealed an inverse correlation between renal cell carcinoma expression of PD-L1 and survival (57), and identified PD-L1 as a prognostic indicator of poor survival for urothelial carcinoma patients receiving BCG therapy (58). The differences between these reports could be due to differences between different types of cancer.…”

Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review

“…In addition, 95% of lymphocytes that invade bladder tumors express the PD-1 receptor [12,148]. Urothelial expression of PD-L1 was also predictive of mortality following cystectomy in patients with organ-limited disease [12,148]. These results have pointed the PD-L1/PD-1 pathway as an attractive therapeutic target for bladder cancer treatment.…”

“…PD-L1 is expressed by 12% of bladder tumor cells, 27% of tumor infiltrating immune cells and in up to 50% of malignant urothelial cells in CIS [12,148]. In addition, 95% of lymphocytes that invade bladder tumors express the PD-1 receptor [12,148]. Urothelial expression of PD-L1 was also predictive of mortality following cystectomy in patients with organ-limited disease [12,148].…”

“…Tumor cells overexpress PD-L1 following T cells infiltration, therefore, evading T cell-mediated immune eradication ( Figure 6). PD-L1 is expressed by 12% of bladder tumor cells, 27% of tumor infiltrating immune cells and in up to 50% of malignant urothelial cells in CIS [12,148]. In addition, 95% of lymphocytes that invade bladder tumors express the PD-1 receptor [12,148].…”

Blockade of the Checkpoint as New Target of the Immunotherapy in the Treatment of Cancer.

“…In various studies expression of PD-L1 by many different tumors has been reported (1)(2)(3)(4) . Based on this finding, recently, development of agents inhibiting the interaction between PD-1, and PD-L1 has become a promising advancement in the treatment of cancer patients (1)(2)(3)(4)(5)(6)(7) . These agents have exerted potent effects with minimal toxicity, and prolonged survival.…”