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

Abstract

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.

Association of cancer progression with elevated expression of programmed cell death protein 1 ligand 1 by upper tract urothelial carcinoma and increased tumor-infiltrating lymphocyte density

“…In contrast, we observed that UC patients with type II tumors (low tumor cell PD-L1 expression and low TILD) had a lower histological grade and lower pT stage than the other three groups, as well showing a favorable prognosis. Similarly, it has been reported in BUC that lower PD-L1 expression by tumor cells and a lower TILD are related to higher histological differentiation, noninvasiveness, and better survival [23]. Thus, our findings in UTUC may be in the same line than those in BUC in general.…”

“…In the present study, slides of full-face hematoxylin and eosin-stained sections from primary tumors were retrieved for the evaluation of TILs by light microscopy [22,23]. Therein, we observed many mononuclear inflammatory cells in variable proportions, such as a small rounded cell and a large dark-stained nucleus with little eosinophilic cytoplasm.…”

“…All the 1000 tumor cells, from each patient, were counted in a high-power view by two of the authors independently (Nukui and Kamai). Furthermore, depending on the level of PD-L1 expression, we classified the tumors into two groups, namely a high expression group (> 5% positive tumor cells and > 5% positive TILs) and a low expression group (< 5% positive tumor cells and > 5% positive TILs) [23,26].…”

A pooled analysis of the prognostic value of PD-L1 in melanoma: evidence from 1062 patients

“…Exosomal microRNAs (miRNAs), which are transferred by EVs, are promising and reliable tools for cancer diagnosis and clinical application [18]. PD-L1 overexpression has been examined as a prognostic factor in diverse cancers including lung cancer [19], gastric cancer [20], ovarian cancer [21], breast cancer [22], prostate cancer [23], bladder cancer [24], cervical cancer [25], cholangiocarcinoma [26], colorectal cancer [27], nasopharyngeal carcinoma [28], diffuse large B-cell lymphoma [29], pancreatic cancer [30], soft-tissue sarcoma [31], renal cell carcinoma [32], and head and neck squamous cell carcinoma [33]. In addition, in patients with melanoma, exosomal PD-L1 is an indicator of immune activation early after the initiation of treatment with immune checkpoint inhibitors (ICIs) and is associated with clinical response to ICIs [34].…”

Expression of PD-L1 in tumor and immune system cells affects the survival of patients with urinary bladder cancer

“…Their studies indicated, however, that high heterogeneity of expression dependent on the type of cells expressing PD-L1 cells may lead to unreliable results [40]. Recent studies suggest that not only the level of PD-L1 expression in IECs may have a prognostic value but also their location and aggregation within the tumor may significantly affect survival [41,42]. Our findings indicate that there is a significant prognostic value of assessing the dispersed and aggregated patterns of distribution of PD-L1+ IECs within the tumor.…”