PD-L1 expression in tumor-infiltrating lymphocytes (TILs) as an independent predictor of prognosis in patients with pN0 bladder cancer undergoing radical cystectomy.

Checkpoint inhibitors have led to a paradigm shift in urothelial carcinoma (UC) treatment. However, the relationship between PD-L1 expression status and oncological outcomes in UC patients remains uncertain. Here, we investigated the prognostic value of PD-L1 expression status in patients with UC of the bladder (UCB) who underwent radical cystectomy (RC). We retrospectively analyzed pathological specimens from 97 UCB patients treated with RC from 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining using SP263 was performed to evaluate PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). Kaplan-Meier plots and proportional Cox hazard ratios were examined to assess the relationship between PD-L1 expression and clinicopathological parameters and survival outcomes. Of the 97 specimens, 19.5% contained PD-L1-positive TCs, and 35.0% contained PD-L1-positive TILs. Regarding clinicopathological factors, PD-L1-positive TCs and TILs were significantly associated with high-grade tumors (TCs, P = 0.01; TILs, P = 0.003). Kaplan-Meier analyses showed that PD-L1-positive TCs were not correlated with survival rates. However, PD-L1-positive TILs were significantly associated with better recurrence-free survival (RFS; P = 0.03) and better cancer-specific survival (CSS; P = 0.02). Univariate analysis, but not multivariate analysis, CSS indicated that PD-L1-positive TILs were significant predictors of patient prognoses. Multivariate analysis showed that PD-L1-positive TILs independently predicted CSS in patients without lymph node metastasis (pN0). Positive PD-L1 expression is associated with high-grade tumors. PD-L1-positive TILs are independent predictors of favorable survival outcomes in surgically resected UCB patients at stage pN0.

Murakami Y ，Matsumoto K ，Shimizu Y ，Ikeda M ，Amano N ，Shimura S ，Ishii D ，Sato Y ，Iwamura M ... -  《-》

Relationship between survival outcomes and microsatellite instability, tumor infiltrating lymphocytes and programmed cell death ligand-1 expression in patients with bladder cancer and radical cystectomy.

Tural D ，Akar E ，Baytekin HF ，Canoglu D ，Yilmaz M ，Tugcu V ... -  《-》

High PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor in urothelial carcinoma.

Zhong Q ，Shou J ，Ying J ，Ling Y ，Yu Y ，Shen Z ，Zhang Y ，Li N ，Shi Y ，Zhou A ... -  《-》

Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder.

Drugs blocking programmed death ligand-1 (PD-L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD-L1 with tumor-infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8+ TIL, Th1 orientation T cell (T-bet+ ) and PD-1+ TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD-L1 expression in tumor cells and 55% in tumor-infiltrating immune cells. CD8+ TIL, T-bet+ TIL and PD-1+ TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD-L1+ tumor cells and PD-L1+ immune cells were positively associated with aggressive clinical features (all P < .05). Both PD-L1+ tumor cells and PD-L1+ immune cells were associated with poorer recurrence-free and overall survival (all P < .05). Multivariate analysis showed that PD-L1+ immune cells were an independent prognostic factor for overall (P = .001) and recurrence-free survival (P = .024). Notably, high stromal CD8+ TIL and PD-1+ TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8+ TIL density has strong positive association with PD-L1+ immune cells and PD-1+ TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune-checkpoint inhibitors may be effective for resectable patients with UCB.

Wang B ，Pan W ，Yang M ，Yang W ，He W ，Chen X ，Bi J ，Jiang N ，Huang J ，Lin T ... -  《-》

Expression and prognostic utility of PD-L1 in patients with squamous cell carcinoma of the bladder.

Checkpoint inhibitors are approved for the treatment of urothelial bladder cancer. However, there have been no reports on the prognostic value of programmed-death receptor ligand 1 (PD-L1) expression in squamous cell carcinoma (SCC) of the bladder. We assessed the relationship between PD-L1 expression, clinicopathological features, and oncologic outcomes in bladder SCC. Immunohistochemistry of PD-L1 was performed on 151 radical cystectomy specimens with pure SCC treated in Mansoura, Egypt from 1997 to 2004. Median patient age was 52 years (range: 36-74 years) and median length of follow up was 63 months (range: 1-100 months). Schistosomiasis was present in 81% of the specimens and 93% had muscle-invasive disease on pathologic staging. PD-L1 expression was negative in 50 (33%) of the specimens. Negative PD-L1 expression was associated with higher pathologic tumor stage (P = 0.04), higher grade lesions (P = 0.01), and the presence of lymphovascular invasion (P < 0.01). Kaplan-Meier analyses showed that negative PD-L1 expression is associated with worse recurrence-free (P = 0.01) and worse cancer-specific survival (P = 0.01). Multivariable Cox regression analyses showed negative PD-L1 expression was an independent predictor of disease recurrence (hazards ratio 2.05, 95% confidence interval 1.06-3.96, P = 0.03) and cancer-specific mortality (hazards ratio 2.89, 95% confidence interval 1.22-6.82, P = 0.02). Negative PD-L1 expression is associated with higher pathologic tumor stage, higher grade lesions, presence of lymphovascular invasion, and worse oncologic outcomes after radical cystectomy for SCC. These findings support the need for the inclusion of patients with bladder SCC into immunotherapy clinical trials.

Owyong M ，Lotan Y ，Kapur P ，Panwar V ，McKenzie T ，Lee TK ，Zi X ，Martin JW ，Mosbah A ，Abol-Enein H ，Ghoneim M ，Youssef RF ... -  《-》