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IL-6-induced CD39 expression on tumor-infiltrating NK cells predicts poor prognosis in esophageal squamous cell carcinoma

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Abstract

Natural killer (NK) cells, a predominant innate lymphocyte subset, mediates eradicating malignant cells. Purinergic signaling by ectonucleotidase CD39 can suppress T-cell response in caner. However, the role of CD39 in NK cells has not been fully elucidated. Here, we characterized CD39 expression on NK cells and its clinical relevance in esophageal squamous cell carcinoma (ESCC). Peripheral blood and tissue samples were collected from 36 ESCC patients. We observed that the proportion of NK cells significantly decreased but CD39 was obviously up-regulated on NK cells from cancerous tissues compared to paired peripheral blood in ESCC patients. Furthermore, tumor-infiltrating NK cells with high CD39 expression exhibited a phenotype of functional impairment. In vitro, conditioned media of ESCC cell lines could induce CD39 expression on peripheral NK cells from healthy donors. IL-6 was identified as the major cytokine produced by ESCC cell lines and also elevated in both tumor tissues and blood serum from ESCC patients. Recombinant IL-6 significantly induced surface CD39 expression in human NK cells, while IL-6-receptor antagonist tocilizumab prevented this effect. Finally, tumor-infiltrating CD39+ NK cells were correlated with poor prognosis in ESCC patients. Thus, tumor-derived IL-6 might impair NK cell functions through induction of CD39 expression. CD39+ NK cells may serve as a potential prognostic biomarker for ESCC patients.

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Abbreviations

CM:

Conditioned media

ESCC:

Esophageal squamous cell carcinoma

NK:

Natural killer

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death 1

PD-L1:

Programmed death ligand 1

PMA:

Phorbol 12-myristate 13-acetate

TIGIT:

T cell immunoglobulin and ITIM domain

TIL:

Tumor infiltrating lymphocytes

Tim-3:

T cell immunoglobulin and mucin domain-containing protein 3

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81773045). We thank our laboratory members for their fruitful discussion.

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Author notes

  1. Yujia Zheng and Yu Li contributed equally to this work.

Authors and Affiliations

  1. Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, People’s Republic of China

    Yujia Zheng, Yu Li, Bo Tang, Qitai Zhao, Dan Wang, Yulin Liu, Mengxing Guo, Yi Zhang & Lan Huang

  2. Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China

    Song Zhao & Yu Qi

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  1. Yujia Zheng
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Contributions

LH, and YZ conceived and designed the study. YJZ, YL, BT and QTZ conducted experiments and data analysis. WD, MXG, SZ and YQ performed sample collection and analysis. LH and YJZ wrote the manuscript. All the authors approved the manuscript.

Corresponding authors

Correspondence to Yi Zhang or Lan Huang.

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Authors declare no conflicts of interest for this article.

Ethical approval

The study has been approved by the Institutional Ethical Committee of the First Affiliated Hospital of Zhengzhou University, China (no. 2016-LW-52), and performed in accordance with the ethical standards as laid down in the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all participants included in the study.

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Zheng, Y., Li, Y., Tang, B. et al. IL-6-induced CD39 expression on tumor-infiltrating NK cells predicts poor prognosis in esophageal squamous cell carcinoma. Cancer Immunol Immunother 69, 2371–2380 (2020). https://doi.org/10.1007/s00262-020-02629-1

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