Abstract
BackgroundRecurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown.MethodsSingle cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 μm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics.ResultsThe percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively.ConclusionsTumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.
Highlights
Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC)
The percentage of natural killer cells is increased in the peripheral blood and tissues of patients with oesophageal squamous cell carcinoma To evaluate the potential roles of Natural killer (NK) cells in human oesophageal squamous cell carcinoma, we first analysed the percentage of NK cells in the peripheral blood, tumour tissues and matched adjacent tissues of 35 healthy volunteers or 52 patients (Fig. 1a)
Convincing evidence has revealed that CD56dim NK cells are mainly distributed in peripheral blood for immune surveillance and that CD56bright NK cells are mainly located in tissues for immunomodulation via cytokine secretion [12]
Summary
Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Epidemiological studies have shown that most patients with ESCC die from tumour recurrence and metastases, but the underlying mechanism remains to be clarified [2]. Immunotherapy, such as Car-T and PD-1/PD-L1 antibodies, has been applied to tumour therapy with far-reaching impact as a new therapeutic strategy [3, 4]. Large numbers of lymphocytes have been found to infiltrate tumour tissues for immune surveillance, but tumour cells develop multiple mechanisms to escape immune surveillance [5,6,7,8]. One important reason for this lack of improvement is that the function of tumour-infiltrating NK cells could be impaired by the tumour microenvironment [16]
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