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Glioma is one of the most aggressive human cancers with limited therapeutic options. Though research has extensively examined immune components in those malignant tumors, the pathophysiological mechanism establishing their immunosuppressive microenvironment remains incompletely characterized. In this study, we report for the first time the unique presence of tumor-specific neutrophils (TSNs) in human glioblastoma (GBM) tumors. This newly defined neutrophil subtype exhibits the high expression of several immunosuppressive genes (e.g., CD274 and IDO1) and is strongly correlated with glioma grades and poor prognosis of patients. TSNs with comparable gene signatures are similarly present in the tumors but not bone marrow or spleen of mouse glioma models. Blockage of TSN recruitment by either Cxcl1-knockout in glioma cells or Cxcr2-deletion in host mice significantly enhances antitumor immunity and inhibits tumor progression. Surprisingly, we further discover the meninges as the key extratumoral source of generating TSNs in both human GBM patients and mouse glioma models. These results have therefore elucidated a novel mechanism designating the tumor microenvironment of gliomas and its essential link to meningeal immunity.

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