Shule Chen,1,* Jie Meng,2,* Lei Liu,3,* Peilu Huang,3,* Zhichao Xie,1 Zhiguo Zhang,1 Sansheng Ma,1 Yichuang Huang,1 Chunhua Bei,4 Lingyun Liu1 

1Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China; 2Department of Health Management Center, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, Liuzhou Workers’ Hospital, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, 545007, People’s Republic of China; 4Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, School of Public Health, Guilin Medical University, Guilin, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chunhua Bei; Email chunhuabei@glmc.edu.cn Lingyun Liu, Email allllyy@163.com

Objective: PD-L2 is expressed in various cancer tissues. Currently, the value of PD-L2 expression in intrahepatic cholangiocarcinoma (ICC) tissues remains unclear. This study investigated the prognostic and clinical significance of PD-L2 expression in ICC.
Methods: This research employs The Cancer Genome Atlas (TCGA) database to examine the expression profiles of PD-L2 in ICC and to evaluate its prognostic significance. Immunohistochemistry detected PD-L2 expression in 66 postoperative ICC tissues and paired adjacent tissues. Correlations between PD-L2 expression and clinicopathological data were analyzed. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the prognostic value of PD-L2.
Results: Bioinformatics analysis shows that high expression of PD-L2 dominates in early ICC patients and is closely associated with tumor recurrence. High PD-L2 expression is associated with longer progression free survival (PFS) (P=0.015). Immunohistochemistry confirmed that the expression of PD-L2 was significantly increased in tumor tissue compared to surrounding tissue. Overexpression of PD-L2 is associated with early TNM staging (P=0.014). Univariate analysis identified preoperative symptoms, number of tumors, tumor size, tumor differentiation, peritumoral integrity, surgical margins, TNM stage, and preoperative CA125 level as associated with overall survival (OS) (all P < 0.05). Preoperative symptoms, number of tumors, peritumoral integrity, surgical margins, TNM stage, preoperative CA125, and PD-L2 expression were associated with disease-free survival (DFS) (all P < 0.05). Multivariate analysis determined tumor differentiation and TNM stage as independent prognostic factors for OS (both P < 0.05). Surgical margins and PD-L2 expression levels were independent prognostic factors for DFS (both P < 0.05).
Conclusion: PD-L2 expression is predominantly high in patients with early-stage ICC. PD-L2 expression serves as an independent predictor of DFS in patients with ICC following hepatectomy. ICC patients with elevated PD-L2 expression levels exhibit delayed relapse.

Keywords: intrahepatic cholangiocarcinoma, programmed death ligand-2, immunohistochemistry, bioinformatics, prognosis