Neutrophils Correlate with Hypoxia Microenvironment and Promote Progression of Non-Small-Cell Lung Cancer

Abstract Background: Hypoxia, a strong and selective pressure, has been involved in invasion, metastasis, and angiogenesis of tumor cells. Methods: Our study performed the transcriptome profiles of 666 non-small-cell lung cancer (NSCLC) patients with clinical parameters from 3 microarray datasets. Various bioinformatic approaches were combined to evaluate the immune cell infiltration in the high hypoxia risk patients. In addition, in vitro experiments were performed to assess the effects of TANs on NSCLC cells proliferation, migration and invasion and to reveal the underlying mechanisms.Results: To develop a prognostic prediction model for NSCLC patients, we divided NSCLC into two groups (Cluster1/2) based on the expression profiles of hypoxia-associated genes. Compared with the Cluster1 subgroup, the Cluster2 had a worse prognosis. Significant enrichment analysis revealed that PI3K/AKT/mTOR signaling pathway and tumor-associated neutrophils (TANs) were highly related to hypoxia microenvironment. Eleven hypoxia-related genes were scored by LASSO COX regression to yield risk scores, and we revealed a significant difference in overall survival (OS) between the low- and high-risk groups. The receiver operating characteristic (ROC) curve and calibration curves suggested that the risk score can predict survival in NSCLC. Mechanistically, CXCL6 in hypoxic cancer cells promoted the migration of TANs in vitro, and in turn promote NSCLC cells proliferation, migration and invasion. Conclusions: In summary, this study revealed a 11‐hypoxia gene signature that predicted OS of NSCLC patients, and improved our understanding of the role of TANs in hypoxia microenvironment.