TGF-β1 and IL-17A comediate the protumor phenotype of neutrophils to regulate the epithelial-mesenchymal transition in oral squamous cell carcinoma.

Abstract

The role of neutrophils in cancer has been the subject of intense research in recent years. One major theme that has emerged is that not all neutrophils are equal in the field of cancer. However, it remains unclear what induces the protumorigenic or antitumorigenic phenotype predominate in tumor. Therefore, this study aimed to investigate what factors induce which of these two phenotypes of neutrophil predominate in OSCC and to explore the role of neutrophil polarization on tumor. Immunofluorescence and immunohistochemistry staining were used to observe neutrophil infiltration and the expression of TGF-β1 and IL-17A in OSCC tissues. Recombinant human TGF-β1 and IL-17A were used to modulate neutrophil polarization. OSCC cell (SCC9 and SAS cell lines) migration, proliferation, invasion, stemness, and EMT were analyzed after treatment with conditioned medium from TGF-β1/IL-17A-activated neutrophils. The levels of neutrophil-associated markers in OSCC tissues and peripheral blood were examined by immunofluorescence staining and quantitative PCR. Our data showed neutrophil infiltration and elevated expression of TGF-β1 and IL-17A in OSCC tissues. The cooperative effect of TGF-β1 and IL-17A promoted neutrophils to take on a protumor phenotype in vitro. TGF-β1/IL-17A-activated neutrophils remarkably induced cell migration, proliferation, invasion, stemness, and EMT in OSCC cells. Additionally, OSCC patients showed increased expression of MMP9 and decreased expression of CCL3 in circulating neutrophils. TGF-β1 and IL-17A cooperated to augment the protumor functions of neutrophils, thereby promoting the progression of OSCC cells. In addition, the combination of neutrophil-associated markers may serve as a predictive method to screen for patients with OSCC.