Abstract
The chemokine CXCL8 has been found to play an important role in tumor progression in recent years. CXCL8 activates multiple intracellular signaling pathways by binding to its receptors (CXCR1/2), and plays dual pro-tumorigenic roles in the tumor microenvironment (TME) including directly promoting tumor survival and affecting components of TME to indirectly facilitate tumor progression, which include facilitating tumor cell proliferation and epithelial-to-mesenchymal transition (EMT), pro-angiogenesis, and inhibit anti-tumor immunity. More recently, clinical trials indicate that CXCL8 can act as an independently predictive biomarker in patients receiving immune checkpoint inhibitions (ICIs) therapy. Preclinical studies also suggest that combined CXCL8 blockade and ICIs therapy can enhance the anti-tumor efficacy, and several clinical trials are being conducted to evaluate this therapy modality.
Highlights
The chemokine CXCL8, known as interleukin-8 (IL-8), is initially known as a cytokine expressed by epithelial cells and macrophages for neutrophil recruitment to areas of inflammation, infection, or injury (Horn et al, 2020a)
Two studies conducted in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma indicated that mesenchymal stem cells (MSCs) and cancerassociated fibroblasts (CAFs) could promote cancer cells secreting CXCL8, enhancing the ability of proliferation and invasion (Wang et al, 2015; Awaji et al, 2019)
CXCL8 level is associated with poor clinical outcomes in participants with advanced melanoma, non-small-cell lung cancer (NSCLC), and renal-cell carcinoma (RCC) treated with nivolumab or ipilimumab, everolimus or docetaxel, which indicate that serum CXCL8 level is an unfavorable factor in tumor immunobiology and can act as an independently predictive biomarker in patients receiving Immune checkpoint inhibitions (ICIs) (Schalper et al, 2020)
Summary
The chemokine CXCL8, known as interleukin-8 (IL-8), is initially known as a cytokine expressed by epithelial cells and macrophages for neutrophil recruitment to areas of inflammation, infection, or injury (Horn et al, 2020a). Upon CXCL8 binding, CXCR1/2 can active multiple G-protein-mediated signalling cascades (Figure 2). As a result of promoting these upstream signaling pathways, including PI3K/Akt, MAPK, and PLC/PKC, the activation of numerous transcription factors would be induced, one of which was nuclear factor-κB (NF-κB) (Waugh and Wilson, 2008; Gales, et al, 2013). Numerous studies have confirmed that CXCL8 can induce the phosphorylation of protein tyrosine kinases, including FAK and Src kinases (Waugh and Wilson, 2008; Liu et al, 2016; Ju et al, 2017; Mohamed et al, 2020). Increased studies evidence that CXCL8 can induce the activation of Janus kinases and signal transducer and activator of transcription protein 3 (JAK/STAT3) signaling in both cancer and immune cells (Fu et al, 2015; Guo et al, 2017; Wu et al, 2019; Hu et al, 2020). CXCL8 has already been described as a pro-tumorigenic chemokine by impacting cancer cells and modifying TME to promote tumor progression and metastasis
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