Neutrophils in Gliomas

Abstract

Neutrophils are the most abundant white blood cells and are the first recruited to inflammatory sites. Neutrophils are an important component of the tumor stroma and can exert both anti-tumoral and pro-tumoral activities, depending on their maturation and activation state. In human gliomas, the number of circulating and infiltrating neutrophils correlates with the severity of the disease, indicating a prognostic and possible pro-tumoral role for these leukocytes. In glioma preclinical models, neutrophils promote tumor growth and orchestrate the resistance to anti-angiogenic therapies. Nevertheless, recent data indicate that neutrophils can be activated to directly kill tumor cells or to orchestrate the anti-tumoral response. Here, we review current knowledge about the role of neutrophils in glioma and their possible involvement in new strategies to improve current cancer therapies.

Keywords: cancer immunotherapy; chemokines; glioma; immunotherapy; inflammation and cancer; neutrophils.

Figure 1

The immune response in gliomas. Glioma cells overexpress TGF-β and IL-10, immunosuppressive cytokines that decrease T-cell responsiveness and antigen-presenting cell function. Glioma cells down-regulate MHC-I and upregulate programmed death ligand-1 (PD-L1) expression leading to defective T-cell responsiveness. TCR activity is also dampened through CTLA-4 expression. TGF-β and IL-10 promote the recruitment and differentiation of regulatory T cells. Finally, secretion of CSF-1 and GM-CSF by glioma cells increase macrophage recruitment and polarization to M2-like phenotype.

Figure 2

Circulating and infiltrating neutrophils sustain glioma growth. (A) In glioma patients, high NLR is associated with poor prognosis. Neutrophil activation measured as increased CD11b level, is an early sign of tumor progression. Secretion of Arginase-1 by neutrophil promotes immunosuppression and VEGF-A production induces angiogenesis. (B) Glioma cells attract neutrophils by producing the chemoattractants CXCL8 and MIF. Tumor-associated neutrophils exert their pro-tumoral role expressing elastase that sustains glioma infiltration and S100A4 that increases tumor proliferation rate.