Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection.
OBJECTIVE
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).


METHODS
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.


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 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.


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 tumor-stroma interaction-oriented cancer immunotherapy.
Cai
Ming-Yan
MY
Liver Cancer Institute, Zhong Shan Hospital, Fudan University, Shanghai 200032, People's Republic of China.
Xu
Yong-Feng
YF
Qiu
Shuang-Jian
SJ
Ju
Min-Jie
MJ
Gao
Qiang
Q
Li
Yi-Wei
YW
Zhang
Bo-Heng
BH
Zhou
Jian
J
Fan
Jia
J
D000704:Analysis of Variance; D015153:Blotting, Western; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D015331:Cohort Studies; D006680:HLA Antigens / Q000096:biosynthesis*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I