Human Leukocyte Antigen-G Protein Expression Is an Unfavorable Prognostic Predictor of Hepatocellular Carcinoma following Curative Resection

Abstract

Purpose: Human leukocyte antigen-G (HLA-G) is a tumor-associated immunosuppressive molecule involved in tumor escape mechanisms.The aim of this study is to elucidate its prognostic significance in hepatocellular carcinoma (HCC). Experimental Design: Immunohistochemical staining of HLA-G expression as well as tumorinfiltrating FoxP3 + regulatory (Tregs) and CD8 + cytotoxic T cells was carried out on tissue microarrays containing 173 HCC tissue specimens. Membrane-bound HLA-G1protein expression in five human HCC cell lines was detected by Western blot. Results: HLA-G expression was associated with HCC prognosis, especially in early-stage diseases, with high expression independently associated with shortened overall survival (P = 0.041) and increased tumor recurrence (P = 0.023). HLA-G level was positively related toTregs/CD8 + ratio and their combination served as a better prognosticator, patients having concurrent high levels of both variables at more than three times of risk of death and tumor relapse than those with concurrent low levels (both P < 0.001). In addition, HLA-G1expression increased in a concordant manner with the increase of metastatic potential in human HCC cell lines. Conclusions: Overexpression of HLA-G protein in HCC was an independent indicator for poor outcome especially in early-stage disease. The combination of HLA-G expression and Tregs/ CD8 + ratio added the prognostic power to both variables, offering a possible strategy of tumorstroma interaction-oriented cancer immunotherapy.

Human leukocyte antigen‐G expression is associated with a poor prognosis in patients with esophageal squamous cell carcinoma

“…15 In HCC, HLA-G expression was strongly correlated to advanced disease stage and a poor prognosis. 24,25 Also, breast cancer patients with HLA-G-positive expression had a shorter disease-free survival time. 28 Other studies also revealed that there was significant correlation between HLA-G expression and poor clinical outcomes in lung, gastric and colorectal tumors.…”

“…23 It has also been reported that the status of HLA-G expression or sHLA-G levels in plasma was correlated with certain clinicopathological parameters in malignancies such as hepatocellular carcinoma (HCC), 24,25 nonsmall-cell lung cancer (NSCLC), 15,26,27 breast cancer, 28 endometrial carcinoma, 29 B-cell chronic lymphocytic leukemia (B-CLL), 30 gastric carcinoma and colorectal cancer. 31,32 These studies indicated that HLA-G might serve as a clinical marker in the diagnosis or prediction of clinical outcomes for malignant diseases.…”

Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy

“…However, more studies on the complete HLA-G gene and its linkage disequilibrium with other genes and on HLA-G expression at both the tumor site and plasma in a specific microenvironment are required to consolidate these findings. carcinoma (69,70), esophageal squamous cell carcinoma (71)(72)(73)(74), gastric cancer (75)(76)(77), glioblastoma (78), hepatocellular carcinoma (79)(80)(81), lung cancer (82)(83)(84), nasopharyngeal carcinoma (85), oral cavity squamous cell carcinoma (86), ovarian cancer (87-89), pancreatic adenocarcinoma (90), thyroid carcinoma (91,92). These data were summarized in Table 1.…”

Molecular Pathways: Human Leukocyte Antigen G (HLA-G)

“…It is less frequent in cervical cancer (50). In digestive tumors, HLA-G expression was described in esophageal squamous cell carcinoma (51), colorectal cancer (52), gastric cancer (53), and liver cancer (54). In relation to increased HLA-G expression in cancer, an increase of circulating sHLA-G concentrations was described in patients suffering from different types of cancer (55), and the source of this protein can be either the tumoral cells or the reactive immune cells.…”