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Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection

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Abstract

Tumor-infiltrating lymphocytes (TILs) represent the host immune response to cancer. CD8+ cytotoxic T cells (CTLs) have a central role in the elimination of tumors, while regulatory T cells (Tregs) can suppress the immune reaction. The aim of this study was to investigate the prognostic value of TILs, especially Tregs and CTLs, in hepatocellular carcinoma (HCC) patients after resection. CD3+, CD4+, CD8+, and FoxP3+ TILs were assessed by immunohistochemistry in tumor tissue from 141 randomly selected HCC patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Kaplan–Meier and Cox regression analysis using the median values as cutoff. The density of intratumoral Tregs (P = 0.040) and peritumoral CTLs (P = 0.004) were an independent factor for overall survival (OS), but not for disease-free survival (DFS). The density of CD3+ and CD4+ TILs, and the prevalence of Tregs and CTLs were associated with neither OS nor DFS. The presence of low intratumoral Tregs with high intratumoral CTLs was a negative independent prognostic factor for OS (P = 0.001), while that of low intratumoral Tregs and low peritumoral CTLs independently correlated with improved DFS (P = 0.008). Moreover, the combined analysis of Tregs and CTLs displayed better prognostic performances than any of them alone. Additionally, higher density of intratumoral Tregs correlated with both the presence of liver cirrhosis (P = 0.025) and increased tumor size (P = 0.050). Tregs within tumor environment are promising prognostic parameters for HCC patients, and their combination with CTLs can predict prognosis more effectively.

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Acknowledgments

This study was supported by the Major State Basic Research Development Program (NO.2009CB522407), the Major National S&T Program (NO. 2008ZX10002-026), and the Program for Innovative Research Team of Zhejiang Province of China (NO. 2009R50038).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China

    Kang-jie Chen, Lin Zhou, Hai-yang Xie, Taki-Eldin Ahmed, Xiao-wen Feng & Shu-sen Zheng

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  1. Kang-jie Chen
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Correspondence to Shu-sen Zheng.

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Handling EiC: Peter Wiernik.

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12032_2011_6_MOESM1_ESM.tif

Fig. 1 Peritumoral tumor-infiltrating lymphocytes (TILs) outnumbered intratumoral TILs. (a) A typical tissue disk. T, tumor tissue; P, peritumor tissue. (b) Peritumoral lymphocytes form an aggregate. In a representative case, (c) in the peritumoral noncancerous area, lymphocytic infiltration was more abundant than that of (d) the intratumoral area. In each case, positive lymphocytes were stained brown (a, x100; b, x200; c and d, x400). (e) The density of FoxP3+ cells in intratumoral area was close to that in peritumoral area. (magnification, x200) (TIFF 10588 kb)

12032_2011_6_MOESM2_ESM.tif

Fig. 2 Kaplan–Meier analyses of disease-free survival and overall survival for intratumoral CD3+ (CD3I; a and b) and CD4+ (CD4I; c and d) TILs, and the prevalence of intratumoral CTLs among intratumoral CD3+ TILs (CD8I/CD3I; e and f) and intratumoral Tregs among intratumoralCD4+ TILs (FoxP3I/CD4I; g and h). None of them was associated with survival and recurrence (TIFF 2311 kb)

12032_2011_6_MOESM3_ESM.tif

Fig. 3 Kaplan–Meier pairwise analyses of disease-free survival and overall survival for the combination of intratumoral Tregs (FoxP3I) with intratumoral CTLs (CD8I) and with peritumoral CTLs (CD8P) (TIFF 1924 kb)

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Supplementary material 7 (DOC 53 kb)

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Chen, Kj., Zhou, L., Xie, Hy. et al. Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med Oncol 29, 1817–1826 (2012). https://doi.org/10.1007/s12032-011-0006-x

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  • DOI: https://doi.org/10.1007/s12032-011-0006-x

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