FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis

Noritoshi Kobayashi, Nobuyoshi Hiraoka, Wataru Yamagami, Hidenori Ojima, Yae Kanai, Tomoo Kosuge, Atsushi Nakajima, Setsuo Hirohashi

Research output: Contribution to journalArticle

286 Citations (Scopus)

Abstract

Purpose: 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 + Tcells during hepatocarcinogenesis. Experimental Design: 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 non-tumorous 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.

Original languageEnglish
Pages (from-to)902-911
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number3
DOIs
Publication statusPublished - 2007 Feb 1
Externally publishedYes

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Regulatory T-Lymphocytes
Hepatocellular Carcinoma
Liver
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Neoplasms
Hepatitis Viruses
Cholangiocarcinoma
Virus Diseases
Liver Neoplasms
Hepatitis
Adenocarcinoma
Research Design
Multivariate Analysis
Survival Rate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. / Kobayashi, Noritoshi; Hiraoka, Nobuyoshi; Yamagami, Wataru; Ojima, Hidenori; Kanai, Yae; Kosuge, Tomoo; Nakajima, Atsushi; Hirohashi, Setsuo.

In: Clinical Cancer Research, Vol. 13, No. 3, 01.02.2007, p. 902-911.

Research output: Contribution to journalArticle

Kobayashi, N, Hiraoka, N, Yamagami, W, Ojima, H, Kanai, Y, Kosuge, T, Nakajima, A & Hirohashi, S 2007, 'FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis', Clinical Cancer Research, vol. 13, no. 3, pp. 902-911. https://doi.org/10.1158/1078-0432.CCR-06-2363
Kobayashi, Noritoshi ; Hiraoka, Nobuyoshi ; Yamagami, Wataru ; Ojima, Hidenori ; Kanai, Yae ; Kosuge, Tomoo ; Nakajima, Atsushi ; Hirohashi, Setsuo. / FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 3. pp. 902-911.
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AU - Kobayashi, Noritoshi

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AU - Yamagami, Wataru

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AU - Kanai, Yae

AU - Kosuge, Tomoo

AU - Nakajima, Atsushi

AU - Hirohashi, Setsuo

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AB - Purpose: 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 + Tcells during hepatocarcinogenesis. Experimental Design: 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 non-tumorous 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.

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