FOXP3+ Regulatory T Cells Affect the Development and Progression of Hepatocarcinogenesis

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 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.

Associations Between Infiltrating Lymphocyte Subsets and Hepatocellular Carcinoma

“…Previous experimental study reported a similar finding (Kobayashi et al, 2007). Moreover, we also found the frequency of CD3-CD56+, CD3-CD57+ and CD3+CD8+ cells of the patients with the metastasis less than 12 months were lower than those without metastasis.…”

CD4+, IL17 and Foxp3 Expression in Different pTNM Stages of Operable Non-small Cell Lung Cancer and Effects on Disease Prognosis

“…Thus, the immunosuppression is produced. This suggests that high expression of Treg cells can promote the development of tumor, and affect the prognosis for patients (Woo et al, 2001;Gray et al, 2003;Kono et al, 2006;Hiraoka et al, 2006;Kobayashi et al, 2007).…”

FOXP3+ Cell Density in Primary Tumor Has No Prognostic Impact in Patients with Cutaneous Malignant Melanoma

“…Since the amount of FOXP3 + cells did not show association with any of the studied parameters: patient age or gender, tumor thickness, location, histological type, ulceration and, most importantly, the outcome of the disease, as mentioned above, FOXP3 + cell infiltration in the primary tumor does not seem to have a significant impact on the course of the disease in cutaneous melanoma. Previous studies aiming at the clinical relevance of tumor-infiltrating Tregs have given rise to contradictory results, showing correlation with poor outcome in some cancer types [5][6][7][8][9] but no association or even correlation with improved survival in others [10][11][12][13][14][15][16][17]21]. It could be suggested that each tumor type behaves differently in this context [4], depending perhaps on other players on the scene of antitumor immune reactions and their complex functional interrelationships with Tregs as well as with tumor cells.…”

“…Reports on the prognostic role of tumor-infiltrating Tregs are inconclusive; while in some cancer types their increased level has been correlated with poor outcome, as in the case of ovarian, breast, pancreatic and hepatocellular carcinomas [5][6][7][8][9], in others including prostate and renal cancers no significant associations were found [10,11], and in the case of head and neck carcinomas, colorectal cancer, as well as in several lymphoma types a marked infiltration by Tregs showed correlation with improved survival [12][13][14][15][16][17].…”