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

Abstract

Background Increased expression of programmed cell death 1 ligand 1 (PD-L1) by tumor cells is thought to be a mechanism through which solid cancers promote immune tolerance. However, the association between PD-L1 expression and the prognosis of upper urinary tract urothelial carcinoma (UTUC) remains unknown. Methods We examined immunohistochemical PD-L1 expression and the tumor-infiltrating lymphocyte density (TILD) in 79 patients with UTUC who underwent nephroureterectomy. We classified the tumors into four types based on the combination of PD-L1 expression and TILD, and studied the clinicopathological characteristics of these four tumor types. Results Elevated expression of PD-L1 by tumor cells and a higher TILD were associated with a worse histological grade, higher pT stage, and higher peripheral blood neutrophil-to-lymphocyte ratio. Elevated expression of PD-L1 by tumor cells, a higher TILD, and type I, III, or IV tumors with elevated expression of either PD-L1 or TILD showed a positive correlation with poorer differentiation and local invasion. These three variables were associated with shorter progression-free survival and overall survival in univariate analysis, but only the latter was an independent determinant according to multivariate analysis. The patients who had type II tumors with lower PD-L1 expression and a lower TILD showed more favorable survival than the other three groups. Conclusions These findings suggest that PD-L1 expression and TILs in the tumor microenvironment influence the progression of UTUC. Accordingly, it is important to understand the immunologic characteristics of the tumor microenvironment to develop more effective treatment strategies for this cancer. Keywords Programmed cell death 1 ligand 1 (PD-L1) • Tumor-infiltrating lymphocyte (TIL) • Upper tract urothelial carcinoma (UTUC) • Neutrophil-to-lymphocyte ratio (NLR) Abbreviations BUC Urothelial carcinoma of the bladder CD Cluster of differentiation CT Computed tomography CTLA-4 Cytotoxic T-lymphocyte-associated antigen-4 DCs Dendritic cells GC Gemcitabine and cisplatin LVI Lymphovascular invasion MDSC Myeloid-derived suppressor cell MVAC Methotrexate, vinblastine, doxorubicin, and cisplatin NLR Neutrophil-to-lymphocyte ratio OS Overall survival PD-1 Programmed cell death protein 1 PD-L1 Programmed cell death 1 ligand 1 Akinori Nukui and Takao Kamai have equally contributed to this work.

The Prevalence and Prognostic Role of PD-L1 in Upper Tract Urothelial Carcinoma Patients Underwent Radical Nephroureterectomy: A Systematic Review and Meta-Analysis

“…In the study, PD-L1 was related to UTUC in T stage and tumor grade, and similar findings have been indicated in both UTUC and other types of tumors ( 23 , 24 , 32 , 33 ). Results indicated that PD-L1 could not promote the LVI of UTUC, while great heterogeneity existed in the five studies ( 13 , 15 – 17 , 24 ). However, previous studies have demonstrated that high PD-L1 was related to presence of LVI of tumors ( 15 , 34 , 35 ).…”

“…Results of the cumulative meta-analysis indicated that the 95% CIs narrowed as the pooled results gradually moved near the null. In the meta-analysis, five studies reported a high expression rate (>20%) of PD-L1 (15,17,(23)(24)(25), which provided rationality to apply immunotherapy in such cancers. Furthermore, the great variation in the prevalence might be ascribed to the different IHC strategies across studies, including the different cutoff values and diverse primary antibody species, etc.…”

“…We excluded records for the following reasons: article types or not relevant topics (n = 188), studies had few study samples (≤50) or follow-up duration less than 12 months (n = 4), not in English (n = 9), or insufficient survival data (n = 15). Finally, we included eight retrospective cohort studies (1,406 individuals) (13)(14)(15)(16)(17)(23)(24)(25) in the study (shown in Figure 1).…”

“…In recent years, studies have increased dramatically in investigating the association between PD-L1 and survival outcomes in radically resected UTUC patients and the conclusion is still controversial. Some evidence indicated that higher PD-L1 was related to poor survival for UTUC ( 13 , 14 ), while some reported opposing findings ( 15 – 17 ). Therefore, we formulated clinical questions following the PICOS strategy and firstly assessed whether PD-L1 expression (high or low) was related to survival outcomes or the clinicopathological features in UTUC patients after RNU with no restriction to the study designs through a meta-analysis.…”

Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study)

“…Wang 29 reported that high CD4 + T cells and CD8 + T cells could predict improved survival. Conversely, Nukui 30 found that low stromal TIL combined with low PD-L1 expression by TC predicted increased survival. The variations in the results might be attributable to the distinct characteristics of the included populations, the relatively small size of the study samples, heterogeneity of urothelial carcinoma, and the complexity of the underlying immune regulatory pathway.…”