Disease-specific suppressive granulocytes participate in glioma progression

Glioblastoma represents one of the most aggressive cancers, characterized by severely limited therapeutic options. Despite extensive investigations into this brain malignancy, cellular and molecular components governing its immunosuppressive microenvironment remain incompletely understood. Here, we identify a distinct neutrophil subpopulation, termed disease-specific suppressive granulocytes (DSSGs), present in human glioblastoma and lower-grade gliomas. DSSGs exhibit the concurrent expression of multiple immunosuppressive and immunomodulatory signals, and their abundance strongly correlates with glioma grades and poor clinical outcomes. Genetic disruption of neutrophil recruitment in immunocompetent mouse models of gliomas, achieved through Cxcl1 knockout in glioma cells or host-specific Cxcr2 deletion or diphtheria toxin A-mediated neutrophil depletion, can significantly enhance antitumor immunity and prolong survival. Further, we reveal that the skull bone marrow and meninges can be the primary sources of neutrophils and DSSGs in human and mouse glioma tumors. These findings demonstrate a critical mechanism underlying the establishment of the immunosuppressive microenvironment in gliomas. [Display omitted] •Immunosuppressive neutrophils are distinctly present within human and mouse glioma tumors•Neutrophils in glioma tumors express multiple immunosuppressive and immunomodulatory signals•Blockage of neutrophil responses improves the survival in mouse models of lethal gliomas•Neutrophils can be recruited into glioma tumors from the skull bone marrow and the meninges Zhao et al. report the identification and characterization of immunosuppressive neutrophils within human and mouse glioma tumors. The presence of such disease-specific suppressive granulocytes (DSSGs) correlates with glioma grades and poor clinical outcomes. Blockage of DSSGs, which partly originate from the skull bone marrow and meninges, strongly delays tumor progression.