ARID1A Downregulation Predicts High PD-L1 Expression and Worse Clinical Outcome in Patients With Gallbladder Cancer.

Lingxi Nan,Shulong Zhang,Yueqi Wang,Jie Wang,Xiaobo Bo,Changcheng Wang,Houbao Liu

doi:10.3389/fonc.2022.787897

Abstract

BackgroundRecent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear.MethodsIn total, 224 patients from Zhongshan Hospital were recruited for this retrospective study. The clinicopathological and baseline characteristics of the patients were collected. Bioinformatics analysis was performed to reveal variations in genes and signaling pathways, and ARID1A and PD-L1 expression and the number of PD1+ tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemical staining.ResultsARID1A expression was negatively correlated with overall survival in patients with GBC, and multivariate analysis identified ARID1A as an independent prognostic factor for overall survival. A heatmap and gene set enrichment analysis suggested that cytotoxic T lymphocyte signatures and immune-related signaling pathways were downregulated in ARID1A low tumors. Subsequent immunohistochemical staining confirmed that ARID1A expression was negatively correlated with PD-L1 expression and PD1+ TILs in the tumor microenvironment. The Kaplan–Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ TIL counts is associated with the best prognosis in patients with GBC.ConclusionARID1A inactivation can lead to a worse prognosis in patients with GBC, potentially by mediating immune evasion through the PD1/PD-L1 pathway.

Highlights

Gallbladder cancer (GBC) is a rare malignant tumor of the digestive tract and the most common malignancy of the biliary tract system
The Kaplan–Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ tumorinfiltrating lymphocytes (TILs) counts is associated with the best prognosis in patients with GBC
We conclude that ARID1A expression is significantly correlated with patient prognosis in GBC, whereas high ARID1A expression predicts a better prognosis

Summary

Introduction

Gallbladder cancer (GBC) is a rare malignant tumor of the digestive tract and the most common malignancy of the biliary tract system. The results of gene sequencing illustrated that mutations in the SWI/SNF complex accounted for approximately 20% of mutations in cancers, making it the most frequently mutated tumor suppressor in cancer [5]. The role of ARID1A in tumors has been widely investigated, and ARID1A mutations were commonly observed in multiple cancers [5, 8]. These mutations, which are primarily non-sense or frameshift mutations, can lead to the deficiency of ARID1A and further tumorigenesis [9]. Recent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear

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