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

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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.

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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

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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).

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Author notes

  1. Zheng-Jun Zhou, Hao-Yang Xin, Jia Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China

    Zheng-Jun Zhou, Hao-Yang Xin, Jia Li, Zhi-Qiang Hu, Chu-Bin Luo & Shao-Lai Zhou

  2. Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China

    Zheng-Jun Zhou, Hao-Yang Xin, Jia Li, Zhi-Qiang Hu, Chu-Bin Luo & Shao-Lai Zhou

  3. Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Zheng-Jun Zhou & Shao-Lai Zhou

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  1. Zheng-Jun Zhou
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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.

Corresponding author

Correspondence to Shao-Lai Zhou.

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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.

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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.

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Zhou, ZJ., Xin, HY., Li, J. et al. Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection. Cancer Immunol Immunother 68, 1223–1233 (2019). https://doi.org/10.1007/s00262-019-02355-3

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