The Tumor Microenvironment Promotes Neutrophil Activation in Brain Malignancies

Immunotherapies have limited efficacy in brain tumors, including brain metastases (BrM) and IDH wild-type (WT), high-grade glioblastomas (GBM), and despite significant infiltration of tumor-associated neutrophils (TAN), the functional roles and phenotypes of these TANs remain unknown. To comprehensively investigate neutrophils in patients with primary or metastatic brain malignancies, Maas and colleagues used tumor tissue and matched peripheral blood from patients with glioma or BrMs along with complementary murine models to show that neutrophil content is elevated in IDH WT gliomas and BrMs as compared with low-grade gliomas and nontumor brain tissue, especially near the perivascular niche (PVN), with TANs displaying distinct phenotypes that are altered by the tumor microenvironment (TME). Transcriptomic analyses revealed enrich­ment of proinflammatory signatures in brain neutrophils compared to peripheral blood neutrophils (PBN), which were further enhanced in BrM TANs as compared to TANs from gliomas. Moreover, TANs derived from GBM or BrM mouse models as well as patient samples were found to produce less reactive oxygen species (ROS) compared to PBNs, indicating that the brain TME may protect tumor cells from ROS-induced cytotoxicity. Additionally, brain TANs expressed PD-L1 and accumulated near PD-1–expressing CD8⁺ T cells, suggesting brain TANs may play an immunosuppressive role. Brain TANs were also shown to colocalize with endothelial cells within the PVN and were enriched for angiogenesis-related genes, supporting a proangiogenic function. Furthermore, evaluation of the longevity and transit time of brain TANs in mouse models demonstrated that TANs had increased survival compared to PBNs, and this phenotype was dependent on the TME. Specifically, TNFα and Ceruloplasmin produced by the TME, and not tumor cells themselves, induced these TAN phenotypes, which could be partially reversed by blocking TNFα. Finally, the myeloid compartment, specifically tumor-associated macrophages, most highly expressed these TAN-inducing factors and colocalized with TANs in GBM and BrM tissue samples. In summary, this study discovered a protumor TAN phenotype in brain malignancies that is activated by factors secreted by tumor-associated myeloid cells.

Maas RR, Soukup K, Fournier N, Massara M, Galland S, Kornete M, et al. The local microenvironment drives activation of neutrophils in human brain tumors. Cell 2023;186:4546–66.e27.

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