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Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection

  • Zheng-Jun Zhou
  • Hao-Yang Xin
  • Jia Li
  • Zhi-Qiang Hu
  • Chu-Bin Luo
  • Shao-Lai ZhouEmail author
Original Article

Abstract

Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated the distribution, prognostic value, and potential function of pDCs in HCC patients undergoing curative resection. We performed immunohistochemical analyses of whole tumor sections from 224 patients to assess the expression of BDCA2, CD3, CD4, CD8, Foxp3, granzyme B, IL-17, and CD34. The findings were validated using tissue microarrays from another two independent cohorts totaling 841 HCC patients undergoing curative resection. Our results demonstrated that high numbers of BDCA2+ pDCs within tumors correlated with high alpha-fetoprotein levels, greater vascular invasion, advanced tumor-node-metastasis stage, shorter overall survival, and a higher recurrence rate. However, patient outcomes were not associated with pDCs in peritumoral stromal or nontumor tissues. Furthermore, an increase in intratumoral pDCs was associated with increased intratumoral infiltration of Foxp3+ regulatory T cells and IL-17-producing cells and correlated with tumor vascular density. Univariate and multivariate analyses revealed that the presence of intratumoral pDCs alone or in combination with regulatory T and/or IL-17-producing cells was an independent predictor of time to recurrence and overall survival. In conclusion, our study demonstrated that intratumoral infiltration by pDCs is a novel indicator for poor prognosis in patients with HCC, possibly through the induction of an immune tolerogenic and inflammatory tumor microenvironment comprising regulatory T and IL-17-producing cells. An assessment of the combination of these cells represents a superior predictor of patient outcome.

Keywords

Plasmacytoid dendritic cells Hepatocellular carcinoma Treg cells IL-17 Prognosis 

Abbreviations

AFP

Alpha-fetoprotein

BDCA2

Blood dendritic cell antigen 2

HCC

Hepatocellular carcinoma

HR

Hazard ratio

MVD

Microvessel density

OS

Overall survival

pDCs

Plasmacytoid dendritic cells

TA-pDCs

Tumor-associated pDCs

TNM

Tumor-node-metastasis

Treg

Regulatory T

TTR

Time to recurrence

Notes

Author contributions

Z-JZ, H-YX, and JL performed the experiments; S-LZ and Z-JZ analyzed the data; Z-QH, and C-BL provided the samples; S-LZ and Z-JZ wrote the paper; S-LZ obtained funding and designed the research.

Funding

This study was jointly supported by the National Key R&D Program of China (No. 2018YFA0109400), the National Natural Science Foundation of China (No. 81773069), Shanghai Rising-Star Program (18QA1401200), and Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2018YQ14).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

This study was approved by the Research Ethics Committee of Zhongshan Hospital on February 26th, 2017.

Informed consent

All patients in all three cohorts gave written informed consent to the treatment and the use of their specimens and data for research and for publication.

Supplementary material

262_2019_2355_MOESM1_ESM.pdf (1.6 mb)
Supplementary material 1 (PDF 1630 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiChina
  3. 3.Institute of Biomedical SciencesFudan UniversityShanghaiChina

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