IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

Abstract

Background Recurrence 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. Methods Single 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. Results The 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. Conclusions Tumour 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1310-0) contains supplementary material, which is available to authorized users.

Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?

“…Thus, in the older adult with severe COVID-19, superimposed on a baseline reduction in NKCC and activatory receptor expression would be a SARS-CoV-2 driven induction of functional exhaustion via the up-regulation of NKG2A ( 134 ). Moreover, with in vitro studies having shown that exposure to IL-6 and TNF-α, two cytokines whose circulating levels are elevated in COVID-19 patients ( 3 , 77 , 146 ) impairs NKCC and reduces perforin, NKp30 and NKp46 expression ( 147 – 149 ), then the SARS-CoV-2-induced cytokine storm would exacerbate the abovementioned functional and phenotypical features of NK cell immunesenescence, which would be predicted to further reduce NK cell anti-viral activity.…”

“…However, based on emerging data that suggests excessive pro-inflammatory responses in older adults negatively regulates their immune responses ( 204 , 205 ), we propose the following alternative hypothesis: inflammaging predisposes older adults to severe COVID-19 by suppressing the immune response to SARS-CoV-2 . Whilst in vitro and in vivo studies have demonstrated that exposure to pro-inflammatory cytokines can modulate the phenotype and/or function of innate and adaptive immune cells ( 147 – 149 , 206 ), it is the work of Akbar et al that have specifically linked hyper-inflammation to impaired antigen specific immune responses during aging. Using a human experimental system that investigates antigen-specific immunity in vivo , the group has consistently demonstrated an age-related impairment in the delayed type hypersensitivity (DTH) response to varicella zoster virus (VSV) antigen ( 204 , 205 , 207 ).…”

NKG2A and COVID-19: another brick in the wall

“…19 In addition, it is noteworthy that IL-6 and IL-8, undergoing an increased release in the early phase of COVID-19 infection, impair the functions of NK cells via STAT3-dependent mechanisms, thus contributing to the reduced cytotoxic capacity of these cells. 20 Since it has been widely acknowledged that various leukocytes, including NK and CD8 + cells, can be engaged in bidirectional cross-talk with neutrophils, it is conceivable that an alteration of both the number and function of these cells can compromise their mutual equilibrium. 21 Indeed, it has been well established that contact-dependent interactions, involving neutrophils and NK cells, can stimulate potently the latter cells to produce interferon (IFN)-γ, a versatile cytokine holding a unique position in the antiviral defense system.…”

“…1). In parallel, this scenario could be worsened further by the presence of high IL-6 and IL-8 levels, which can enhance the neutrophil infiltration and activity, 23,24 while holding an inhibitory action on NK cells 20 (Fig. 1).…”

APOC1 is a Potential Prognostic Biomarker and Correlated With Immune Infiltration in ESCC

“…And IL-6 or IL-8 secreted by primary ESCC cells impairs the function of NK cells via the STAT3 signaling pathway. 44 Tumor-associated macrophages (TAMs) have been reported to play a crucial role in in ammatory tumor microenvironment.…”