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

  • 1Department of Surgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
  • 2Department of Pathology, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea


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.
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.
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).
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.


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


  • 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.


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69:7–34. PMID: 30620402.
2. Xu W, Liu K, Chen M, Sun JY, McCaughan GW, Lu XJ, et al. Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives. Ther Adv Med Oncol. 2019; 11:1758835919862692. PMID: 31384311.
3. Jiang Y, Zhan H. Communication between EMT and PD-L1 signaling: new insights into tumor immune evasion. Cancer Lett. 2020; 468:72–81. PMID: 31605776.
4. Zhang SC, Hu ZQ, Long JH, Zhu GM, Wang Y, Jia Y, et al. Clinical implications of tumor-infiltrating immune cells in breast cancer. J Cancer. 2019; 10:6175–6184. PMID: 31762828.
5. Clark WH Jr, Elder DE, Guerry D 4th, Braitman LE, Trock BJ, Schultz D, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989; 81:1893–1904. PMID: 2593166.
6. Xu X, Tan Y, Qian Y, Xue W, Wang Y, Du J, et al. Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore). 2019; 98:e13923. PMID: 30633166.
7. Nam SJ, Kim YH, Park JE, Ra YS, Khang SK, Cho YH, et al. Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma. Cancer Immunol Immunother. 2019; 68:305–318. PMID: 30483834.
8. Du B, Shim JS. Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules. 2016; 21:965. PMID: 27455225.
9. Manjunath Y, Upparahalli SV, Avella DM, Deroche CB, Kimchi ET, Staveley-O’Carroll KF, et al. PD-L1 expression with epithelial mesenchymal transition of circulating tumor cells is associated with poor survival in curatively resected non-small cell lung cancer. Cancers (Basel). 2019; 11:806. PMID: 31212653.
10. Chen L, Xiong Y, Li J, Zheng X, Zhou Q, Turner A, et al. PD-L1 expression promotes epithelial to mesenchymal transition in human esophageal cancer. Cell Physiol Biochem. 2017; 42:2267–2280. PMID: 28848143.
11. Ock CY, Kim S, Keam B, Kim M, Kim TM, Kim JH, et al. PD-L1 expression is associated with epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Oncotarget. 2016; 7:15901–15914. PMID: 26893364.
12. Kim S, Koh J, Kim MY, Kwon D, Go H, Kim YA, et al. PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung. Hum Pathol. 2016; 58:7–14. PMID: 27473266.
13. Dai X, Xue J, Hu J, Yang SL, Chen GG, Lai PB, et al. Positive expression of programmed death ligand 1 in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. Transl Oncol. 2017; 10:511–517. PMID: 28558264.
14. Li JH, Ma WJ, Wang GG, Jiang X, Chen X, Wu L, et al. clinicopathologic significance and prognostic value of programmed cell death ligand 1 (PD-L1) in patients with hepatocellular carcinoma: a meta-analysis. Front Immunol. 2018; 9:2077. PMID: 30254644.
15. Fu J, Zhang Z, Zhou L, Qi Z, Xing S, Lv J, et al. Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology. 2013; 58:139–149. PMID: 22961630.
16. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut. 2012; 61:427–438. PMID: 21930732.
17. Ding W, Xu X, Qian Y, Xue W, Wang Y, Du J, et al. Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore). 2018; 97:e13301. PMID: 30557978.
18. Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019; 25:2279–2293. PMID: 31148900.
19. Gurzu S, Kobori L, Fodor D, Jung I. Epithelial mesenchyma l and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. Biomed Res Int. 2019; 2019:2962580. PMID: 31781608.
20. Jiang Y, Lo AW, Wong A, Chen W, Wang Y, Lin L, et al. Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma. Oncotarget. 2017; 8:30175–30189. PMID: 28404915.
21. Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015; 75:2139–2145. PMID: 25977340.
22. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369:122–133. PMID: 23724867.
23. Yan L, Xu F, Dai CL. Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. J Exp Clin Cancer Res. 2018; 37:203. PMID: 30157906.
24. Bouillez A, Rajabi H, Jin C, Samur M, Tagde A, Alam M, et al. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene. 2017; 36:4037–4046. PMID: 28288138.
25. Alsuliman A, Colak D, Al-Harazi O, Fitwi H, Tulbah A, Al-Tweigeri T, et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer. 2015; 14:149. PMID: 26245467.
26. Hellmann MD, Kim TW, Lee CB, Goh BC, Miller WH Jr, Oh DY, et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann Oncol. 2019; 30:1134–1142. PMID: 30918950.
27. Lee S, Song SK, Bae B, Park Y. Comparing efficacies of different treatment regimens in patients with hepatocellular carcinoma accompanied by portal vein tumor thrombus using network meta-analysis. Ann Surg Treat Res. 2022; 103:280–289. PMID: 36452314.
Full Text Links
  • ASTR
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: