Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

Abstract

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system's response to cancer can impact the glioma's survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

Keywords: glioma; immunosuppression; immunotherapy; inflammation; tumor microenvironment.

FIGURE 1

Schematic of the BBB under (A) homeostasis and (B) glioma-associated inflammation. In inflamed conditions (B), junctions between endothelial cells break apart, pericytes are disrupted, and astrocytic endfeet detach from the basement membrane. Glioma cells, macrophages and microglia, astrocytes, and MDSCs release cytokines and other factors that contribute to BBB breakdown and create an inflammatory tumor microenvironment.

FIGURE 2

Depiction of the immunosuppressive environment in glioblastoma and current therapeutic approaches (red) to stimulate anti-tumor responses or inhibit suppressive immune cell populations. Glioma cells release chemoattractants and cytokines that recruit immune cells into the tumor microenvironment (TME). These factors elicit pro-tumor activities that inhibit effector T cells (Teff) and contribute to tumor progression. Glioma cells can also directly interact with immune cells and astrocytes impacting the effectiveness of chemotherapy. Inhibition of Stat3 by WP1066 reduces glioma-associated macrophages (GAM) by blocking intracellular signals induced by IL-10 to promote an anti-tumor macrophage (M1-like MΦ) phenotype. The CXCR4 antagonist AMD3100 prevents the binding of stromal cell-derived factor (SDF-1), resulting in decreased tumor proliferation and blocks the migration of myeloid-derived suppressor cells (MDSCs) in the TME. The CSF1R inhibitors (PLX3397, BLZ945) suppress the infiltration of myeloid cells (macrophages and MDSCs) within the TME. MDSCs synthesize prostaglandin E2 (PGE2) via COX-2 which inhibits effector T cells by reducing Interferon-gamma (IFN-γ) release. The COX-2 inhibitor, celecoxib reduces MDSC immunosuppressive activity. Interleukin-12 (IL-12) is secreted by antigen-presenting cells (APC) like dendritic cells and macrophages, exogenous IL-12 therapy triggers a pro-inflammatory transition of naïve T cells (ThO) to type 1 helper T cells (Th1) leading to an increase in IFN-y and tumor necrosis factor (TNF-α) secretion. Tumor cells express high levels of programmed cell death ligand (PD-L1) on their cell surface, which leads to exhausted T cells (Tex) by immune checkpoint signaling through their receptor programmed cell death protein 1 (PD-1). Inhibition of PD-1 with nivolumab reduces T cell exhaustion.