Abstract
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). Immunohistochemical staining of HLA-G expression as well as tumor-infiltrating FoxP3+ regulatory (Tregs) and CD8+ cytotoxic T cells was carried out on tissue microarrays containing 173 HCC tissue specimens. Membrane-bound HLA-G1 protein expression in five human HCC cell lines was detected by Western blot. 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 to Tregs/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-G1 expression increased in a concordant manner with the increase of metastatic potential in human HCC cell lines. 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 tumor-stroma interaction-oriented cancer immunotherapy.
Highlights
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)
We reported for the first time that high HLA-G expression was associated with reduced survival and increased recurrence in HCC
Albeit HLA-G group was only significant in Overall survival (OS) by multivariate analysis in all patient population, its independent power was enhanced in predicting both survival and recurrence in early HCC patients indicated by a sharply increased hazard ratio (HR) (3.145 versus 1.987) for death and a gained significance for recurrence
Summary
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). HLA-G expression was positively associated with tumorinfiltrating regulatory/effector T-cell ratio, another immunosuppressive indicator, and their combination was a superior prognosticator. Its restricted distribution in normal tissue and aberrant expression in pathologic conditions, such as tumor and virus-infected cells, suggest that microenvironmental factors control HLA-G expression in injured cells and tissues [19] It has emerged as a tumorderived immunosuppressive molecule with the following abilities: (a) inhibitory function against NK cells, T lymphocytes, and antigen-presenting cells through direct binding to the inhibitory receptors [19] or through ‘‘trogocytosis’’ Contrasting results exist even in patients with the same tumor type, such as gastric cancer [24, 25] and B-cell chronic lymphocytic leukemia [26, 27]
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