Abstract
ABSTRACTInterleukin (IL)-17 has been reported to play a controversial role in tumor immunity. Our previous studies showed that infiltration of IL-17-producing cells in esophageal squamous cell carcinoma (ESCC) induced tumor protective immunity by recruiting CD8+T lymphocytes, natural killer (NK) cells, and B lymphocytes into the tumor microenvironment. However, the mechanism of IL-17 regulation of tumor-associated neutrophils remains elusive in ESCC. In this study, we therefore evaluated the accumulation of myeloperoxidase (MPO)+ neutrophils and its association with IL-17-producing cells within ESCC tumor nests. We also investigated the effects of IL-17 on the recruitment and antitumor activity of neutrophils. MPO+ neutrophil infiltration was found to predict a favorable prognosis in ESCC patients and was positively correlated with IL-17+ cell density. IL-17 stimulated ESCC tumor cells to release more of the CXC chemokines CXCL2 and CXCL3, which are involved in neutrophil migration. Furthermore, IL-17 potentiates the direct killing capability of neutrophils by enhancing the production of cytotoxic molecules, including reactive oxygen species (ROS), MPO, TNF-related apoptosis-inducing ligand (TRAIL), and IFN-γ. Experiments in mice suggested that IL-17 alone might not affect tumor progression in the tumor-bearing host, but IL-17 can inhibit tumor growth by promoting beneficial neutrophil infiltration and activation at tumor sites. As emerging evidence indicates that targeting tumor-associated neutrophils is a strategy for antitumor therapy, our findings reveal a positive contribution of IL-17 to the modulation of neutrophil-mediated antitumor immunity in ESCC. This study provides further understanding of the mechanisms that selectively regulate functional activities of neutrophils, which may be critical for developing new tumor immunotherapy.
Highlights
Esophageal carcinoma is one of the most common cancers, ranking 6th in mortality among all cancers worldwide.[1]
Since our previous studies indicated that IL-17-producing cells within tumor tissues were positively associated with accumulation of CD8C cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which can mediate antitumor responses against Esophageal squamous cell carcinoma (ESCC),[19,20] we investigated whether IL17C cells were related to the infiltration of MPOC neutrophils in the same tumor microenvironment
Studies have begun to emerge showing the significant influence of neutrophils on the tumor microenvironment in a wide variety of human cancers.[24]
Summary
Esophageal carcinoma is one of the most common cancers, ranking 6th in mortality among all cancers worldwide.[1]. It is recognized that the tumor microenvironment plays an important role in controlling tumor development and progression.[5] Accumulating evidence has indicated that tumor cell-extrinsic factors, which include immune cells, fibroblasts, structural molecules, and inflammatory cytokines, are considered to be crucial features in ESCC tumorigenesis.[6,7,8] IL-17A (hereafter referred to as IL-17) is an inflammatory cytokine primarily secreted by Th17 helper cells.[9] Many studies have shown that IL-17 plays a critical role in autoimmune diseases, pathogenesis of inflammatory disorders, and immune responses against bacterial or fungal infections.[9,10] Recently, the function of IL-17 in the tumor microenvironment has been extensively investigated.[11,12] numerous studies suggest that IL-17 can mediate tumor immunity in various types of cancer
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