Classification of gallbladder cancer by assessment of CD8+ TIL and PD-L1 expression

Jianzhen Lin,Xiaobo Yang,Haitao Zhao,Anqiang Wang,Xueshuai Wan,Yan Wu,Simon C Robson,Yi Bai,Xinting Sang,Jingci Chen,Junyu Long

doi:10.1186/s12885-018-4651-8

Abstract

BackgroundProgrammed death ligand 1/2 (PD-L1/PD-L2) expression has been established as a prognostic factor for various solid tumors and as a predictive factor for PD-1 blockade therapy, but scant data on its role in gallbladder cancer (GBC). The aims of this study were to assess the expression of PD-L1/PD-L2 and the density of CD8+ tumor-infiltrating lymphocytes (TIL) from GBC samples and to quantify the association between survival prognosis and these factors.MethodsCD8+ TILs density and the expression of PD-1, PD-L1, PD-L2 and CD133 were assessed using immunohistochemistry in tumor specimens from 66 patients with gallbladder adenocarcinoma. These indexes were correlated with the clinicopathological features.ResultsThe rate of PD-L1-positive (PD-L1+) was 54%, which included 18% positivity in tumor cells, and 36% in peritumoral immune stroma. High CD8+ TIL density (CD8high) was observed in PD-L1+ GBC, and PD-L1+ was positively associated with PD-L2+ expression. Regarding prognostic factors, PD-L1+ expression was related to worse overall survival (OS), and CD8high indicated better OS and progression-free survival (PFS). The combination of CD8high with PD-L1+ serves as a prognostic factor for improved OS (P < 0.001) and PFS (P = 0.014).ConclusionAnalysis of the tumor immune microenvironment based on CD8+ TIL and PD-L1 expression is a promising independent predictor for the clinical outcome of GBC patients.

Highlights

Programmed death ligand 1/2 (PD-L1/PD-L2) expression has been established as a prognostic factor for various solid tumors and as a predictive factor for PD-1 blockade therapy, but scant data on its role in gallbladder cancer (GBC)
We explored the relationships between immune checkpoint markers and both the tumor immune microenvironment (CD8+ tumor-infiltrating lymphocytes (TILs)) and progenitor-like tumor cells (TCs) (CD133+)
We found that PD-L1+ GBC showed a higher probability of positive PD-L2 expression in tumor tissues (83% vs. 47%, P = 0.002) and a 1.54-fold increase in the median CD8+ TIL density (PD-L1+ vs. PD-L1−: 53/field vs. 34.5/field, P = 0.029), whereas no difference in density of the CD8+ TILs existed between PD-L1+ TCs and PD-L1+ immune stroma (IS) (47.5% vs. 57%, P = 0.568)

Summary

Introduction

Programmed death ligand 1/2 (PD-L1/PD-L2) expression has been established as a prognostic factor for various solid tumors and as a predictive factor for PD-1 blockade therapy, but scant data on its role in gallbladder cancer (GBC). The aims of this study were to assess the expression of PD-L1/PD-L2 and the density of CD8+ tumor-infiltrating lymphocytes (TIL) from GBC samples and to quantify the association between survival prognosis and these factors. A satisfactory prognosis of GBC depends on an early diagnosis and completed resection. Immune checkpoint inhibitors that target the programmed death receptor 1/ligand 1 (PD-1/PD-L1) have displayed promising antitumor effects in different types of solid tumors [8,9,10]. Immunohistochemical (IHC) evaluation of PD-L1 is thought to represent a viable method to predict

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