FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis.
OBJECTIVE
Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4+CD25+FOXP3+ regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8+ T cells during hepatocarcinogenesis.


METHODS
We examined the infiltration of FOXP3+ Tregs and CD8+ T cells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies.


RESULTS
The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P<0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P=0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P<0.001) and that of CD8+ T cells decreased during the progression of hepatocarcinogenesis (P<0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors.


CONCLUSIONS
Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.
Kobayashi
Noritoshi
N
Pathology Division, National Cancer Center Research Institute, National Cancer Center Hospital, Tokyo, and Gastroenterology Division, Yokohama City University Hospital, Yokohama, Japan.
Hiraoka
Nobuyoshi
N
Yamagami
Wataru
W
Ojima
Hidenori
H
Kanai
Yae
Y
Kosuge
Tomoo
T
Nakajima
Atsushi
A
Hirohashi
Setsuo
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors