IL-6-induced CD39 expression on tumor-infiltrating NK cells predicts poor prognosis in esophageal squamous cell carcinom
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ORIGINAL ARTICLE
IL‑6‑induced CD39 expression on tumor‑infiltrating NK cells predicts poor prognosis in esophageal squamous cell carcinoma Yujia Zheng1 · Yu Li1 · Bo Tang1 · Qitai Zhao1 · Dan Wang1 · Yulin Liu1 · Mengxing Guo1 · Song Zhao2 · Yu Qi2 · Yi Zhang1 · Lan Huang1 Received: 17 March 2020 / Accepted: 28 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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, tumorinfiltrating 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. Keywords Tumor microenvironment · NK cells · CD39 · Esophageal squamous cell carcinoma Abbreviations CM Conditioned media ESCC Esophageal squamous cell carcinoma NK Natural killer PBMC Peripheral blood mononuclear cells Yujia Zheng and Yu Li contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02629-1) contains supplementary material, which is available to authorized users. * Yi Zhang [email protected] * Lan Huang [email protected] 1
Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, Henan, People’s Republic of China
Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
2
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
Introduction Esophageal cancer is one of the major causes of cancerrelated deaths worldwide that cause more than half a million death each year [1]. Esop
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