NET-producing CD16high CD62Ldim Neutrophils Migrate to Tumor Sites and Predict Improved Survival in Patients with HNSCC

ABSTRACT

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. This study investigated the role of CD16^dim CD62L^high, CD16^high CD62L^high, and CD16^high CD62L^dim neutrophil subsets in head and neck squamous cell carcinoma (HNSCC) patients. These neutrophil subsets may play different roles in immune-related activity in cancer, based upon their profile, activation state, and migration ability within a tumor site, which may be important in predicting cancer prognoses. Tumor biopsies and blood were obtained from newly-diagnosed untreated HNSCC patients and healthy controls. Neutrophil subsets and their phenotype were characterized using flow cytometry. Isolated granulocytes were assessed for anti-tumor immune functions. Compared to controls HNSCC patients exhibited increased CD16^high CD62L^dim neutrophils in blood; this subset displayed a distinct phenotype with high expression of CD11b and CD18. This subset was prone to migrate into the tumor facilitated by tumor derived IL-8. Furthermore, IL-8 was also found to activate neutrophils and thereby promoting subset transition. Various assays demonstrated that activated CD16^high CD62L^dim neutrophils inhibited migration, proliferation, and induced apoptosis of FaDu cancer cells. Neutrophil elastase detected in activated CD16^high CD62L^dim neutrophils and tumor biopsies suggested that CD16^high CD62L^dim neutrophils impart anti-tumoral activity via neutrophil extracellular traps. Furthermore, increased fraction of CD16^high CD62L^dim neutrophils was shown to correlated with an increased survival rate. This study demonstrates the clinical relevance of the CD16^high CD62L^dim neutrophil subset, providing evidence for their increased migration capacity, their anti-tumor activity including increased NET formation and finally their correlation with increased survival in HNSCC patients. This article is protected by copyright. All rights reserved.

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