Neutrophils in glioma microenvironment: from immune function to immunotherapy

Abstract

Glioma is a malignant tumor of the central nervous system (CNS). Currently, effective treatment options for gliomas are still lacking. Neutrophils, as an important member of the tumor microenvironment (TME), are widely distributed in circulation. Recently, the discovery of cranial-meningeal channels and intracranial lymphatic vessels has provided new insights into the origins of neutrophils in the CNS. Neutrophils in the brain may originate more from the skull and adjacent vertebral bone marrow. They cross the blood-brain barrier (BBB) under the action of chemokines and enter the brain parenchyma, subsequently migrating to the glioma TME and undergoing phenotypic changes upon contact with tumor cells. Under glycolytic metabolism model, neutrophils show complex and dual functions in different stages of cancer progression, including participation in the malignant progression, immune suppression, and anti-tumor effects of gliomas. Additionally, neutrophils in the TME interact with other immune cells, playing a crucial role in cancer immunotherapy. Targeting neutrophils may be a novel generation of immunotherapy and improve the efficacy of cancer treatments. This article reviews the molecular mechanisms of neutrophils infiltrating the central nervous system from the external environment, detailing the origin, functions, classifications, and targeted therapies of neutrophils in the context of glioma.

Keywords: glioma; immunotherapy; neutrophil; neutrophil extracellular trap; tumor microenvironment; tumor-associated neutrophils.

Figure 1

The development, recruitment and migration of neutrophils. The most majority of neutrophils in circulation are derived from bone marrow in long bones and the ilium. Starting from HSCs, they undergo several steps of development to become mature neutrophils, which are then released into the circulation. The resident macrophages and epithelial cells secrete chemoattractants to attract neutrophils (e.g. CXCL1, CXCL2, and IL-1α). Through the receptors LFA-4, ICAM-1, VCAM-1 and VLA-4, they migrate to sites of inflammation and exert their anti-bacteria and pathogen-clearing effects. Neutrophils in the brain primarily originate from bone marrow in the skull and adjacent vertebrae, with a smaller proportion derived from circulation. They only cross the BBB or choroid plexus and enter the brain parenchyma under pathological conditions, attracted by chemotactic factors in the TME. Furthermore, factors (e.g. ROS, LCN2, MPO, and MMP9) released by NETs can disrupt the integrity of the BBB, facilitating the infiltration of neutrophils into the brain parenchyma. On the other side, neutrophils also infiltrate the TME through chP under the attraction of CXCL1/2. In the TME, TANs are predominantly found in the central necrotic zone, while TAMs tend to accumulate at the periphery of the tumor. Created with BioRender.com.

Figure 2

The immune responses of TANs in the TME. TANs and their interactions with tumor cells and immune cells constitute a complex TME. Tumor cells attract neutrophils into the TME through various chemokines and secretions. In the early stages of neutrophil entry into the TME, the secretion of NO, MPO, and ROS mediates tumor cell killing. Neutrophils also promote tumor cell death through ADCC and the secretion of H₂O₂. Over time, under the influence of chemokines and secretions in the TME, TANs transition from an anti-inflammatory to a pro-inflammatory phenotype. For example, IL-8 and IL-1β secreted by gliomas promote the formation of NETs through different mechanisms. ROS and lactate secreted by TANs also promote the formation of NETs. TANs associated secretion of NE, MMP9, elastase, and S100A4 plays crucial roles in tumor proliferation, invasion, and angiogenesis. Within the TME, TANs engage in complex interactions with TAMs, NK cells, DCs, T cells, and Tregs. Targeting these receptors is a form of neutrophil-mediated immunotherapy. Neutrophils themselves rely on glycolysis for energy supply and promote the generation of an acidic environment that favors tumor growth. Created with BioRender.com.