Ann Surg Treat Res.  2023 Nov;105(5):297-309. 10.4174/astr.2023.105.5.297.

Prognostic significance of programmed cell death-ligand 1 expression on immune cells and epithelialmesenchymal transition expression in patients with hepatocellular carcinoma

• Jung HI
• Ahn H
• Oh MH
• Yun J
• Lee H
• Bae SH
• Kim YK
• Kim SY
• Baek MJ
• Lee MS

• KMID: 2547535
• DOI: http://doi.org/10.4174/astr.2023.105.5.297

Abstract

Purpose
Immune checkpoint inhibitors (ICIs) have been shown significant oncological improvements in several cancers. However, ICIs are still in their infancy in hepatocellular carcinoma (HCC). Programmed cell death-ligand 1 (PD-L1), tumorinfiltrating lymphocytes (TILs), and epithelial-mesenchymal transition (EMT) have been known as prognostic factors in HCC. Therefore, we have focused on identifying the molecular mechanisms between each marker to evaluate a predictive role.
Methods
Formalin-fixed paraffin-embedded samples were obtained from 166 patients with HCC who underwent surgery. The expression of PD-L1 and TILs and EMT marker were evaluated by immunohistochemical analysis.
Results
The multivariate analysis showed that TIL expression (hazard ratio [HR], 0.483; 95% confidence interval [CI], 0.269–0.866; P = 0.015) were independent prognostic factors for overall survival. The prognostic factors for disease-free survival were EMT marker expression (HR, 1.565; 95% CI, 1.019–2.403; P = 0.005). Patients with high expression of TILs had significantly better survival compared to patients with low expression (P = 0.023). Patients who were TIL+/EMT– showed a significantly better prognosis than those who were TIL–/EMT+ (P = 0.049).
Conclusion
This study demonstrates that PD-L1 expression of TILs is closely associated with EMT marker expression in HCC. Clinical investigations using anti–PD-1/PD-L1 inhibitors in patients with EMT-associated PD-L1 upregulation are warranted.

Keyword

Epithelial-mesenchymal transition; Hepatocellular carcinoma; Prognosis; Programmed cell death 1 ligand 2 protein; Tumor-infiltrating lymphocytes

Figure

• 

  Fig. 1 Representative features of histologic and immunohistochemical analysis in high PD-L1+ immune cells/EMT+ case (A–D) and low PD-L1+ immune cells/EMT– case (E–H). (A and E: H&E stain, ×400; B and F: immunostaining of PD-L1, ×400; C and G: immunostaining of vimentin, ×400; D and H: immunostaining of E-cadherin, ×400). The EMT+ case shows strong cytoplasmic expression of vimentin and loss of membranous staining of E-cadherin and the EMT– case shows no expression of vimentin and strong membranous staining of E-cadherin. PD-L1, programmed cell death-ligand 1; EMT, epithelial-mesenchymal transition.

• 

  Fig. 2 The number of PD-L1+ immune cell-negative (blue bars) and -positive (green bars) cases according to epithelial-mesenchymal transition (EMT) are shown. The P-value from Fisher exact test is annotated (blue). PD-L1, programmed cell death-ligand 1.

• 

  Fig. 3 Survival analysis according to PD-L1 and epithelial-mesenchymal statuses in hepatocellular carcinoma patients. A Kaplan-Meier plot of overall survival (OS; A, C, E, G, I) and disease-free survival (DFS; B, D, F, H, J) according to PD-L1 expression on immune cells and tumor cells and epithelial-mesenchymal transition (EMT) status. PD-L1, programmed cell death-ligand 1.

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