Even though peripheral inflammation, such as allergic airway inflammation, can be far from the brain parenchyma, there are many ways through which the immune system can communicate with the brain. (A) The Blood-Brain Barrier (BBB) is a semipermeable membrane composed of endothelial cells of the capillary wall, pericytes, with astrocytic end feet encircling the capillary. The BBB restricts access and immune cells can only cross this barrier during inflammation. However, recent discoveries found that other entry points into the brain make communication between the brain parenchyma and the peripheral immune system more dynamic than previously thought. (B) Meningeal lymphatic vessels found in the meningeal layer of the dura mater, allow surveillance of antigens and transport of immune cells in the dura. The main immune cells here are neutrophils, MCs, multiple stages of B cells, monocytes and T cells (C) During extensive neuroinflammation recruited myeloid cells and neutrophils can take a shortcut to the brain. They can migrate via microscopic channels crossing the inner skull cortex and end up in dura. B cells can also enter the dura from the skull bone marrow. (D) The choroid plexus located in the ventricles consists of secretory epithelium producing CSF and is an important site for immune surveillance and this barrier allows circulating immune cells to communicate with resident choroid plexus macrophages and NK cells. (E) The circumventricular organs (CVO) are highly vascularized areas located in the 3rd and 4th ventricle. There is a communication via the blood, brain parenchyma and CSF in the CVOs. (F) The deep cervical lymph nodes are important drainage routes for CNS antigens, where DCs sample antigens and may present these antigens to T cells. (G) The cribriform plate is pierced with small holes in the ethmoid bone. This, together with lymphatic vessels, trigeminal nerves, and olfactory nerves, is believed to allow the transport of CNS antigens and entry of immune cells into the CNS. The subarachnoid lymphatic-like membrane (SLYM)158 which is a fourth meningeal layer, completing the dura, arachnoid, and pia mater, that compartmentalizes the subarachnoid space in the mouse and human brain is not depicted in this Figure. Created with « BioRender.com». Abb. CSF: Cerebrospinal fluid
3.3 Immune-therapeutic approaches
Immunotherapy and targeted therapy are leading areas of innovation for the treatment of primary brain tumours in adults and children. Numerous efforts have been made to integrate immunotherapy into current standards of care for glioblastoma that consists of neurosurgical resection as feasible followed by involved-field radiotherapy and concomitant and maintenance temozolomide alkylating agent chemotherapy.67 In selected patients, treatments targeting specific molecular tumour alterations such as B-raf proto-oncogene (BRAF) mutations or neurotrophic tyrosine receptor kinase (NTRK) fusions may be considered.11 Importantly, a recent phase 3 trial has shown the efficacy of the IDH1/2 inhibitor vorasidenib in IDH-mutant grade 2 glioma.88
Efforts focusing on the antagonism of glioma-associated immunosuppression alone, e.g., blocking the TGF-β pathway89 or PD-1/PD-L1-dependent signalling have not been successful. Three randomized phase III trials have explored the PD-1 antibody nivolumab in newly diagnosed or recurrent90 glioblastoma with91 or without92 O6-methylguanine DNA methyltransferase (MGMT) promoter methylation and all were negative. For newly diagnosed patients, whose tumours are lacking MGMT promoter methylation and thus are resistant to chemotherapy, nivolumab, an immune checkpoint inhibitor, did not work better than temozolomide.92 It was also not superior to placebo in patients with tumours with MGMT promoter methylation who may exhibit higher mutational burden because of chemosensitivity.91 Promising findings for survival were observed when anti-PD-1 antibody, pembrolizumab, was administered in a “neoadjuvant” setting before salvage surgery for recurrent glioblastoma93, though findings await confirmation in a larger study.
Various vaccination approaches have been tested, including single peptide-based vaccines like rindopepimut94 or dendritic cell-based vaccines such as ICT-10795 or DCVax96, without clear efficacy. Novel approaches include recombinant fusion protein composed of a human antibody fragment and human tumour necrosis factor (L19TNF) that use antibodies directed against embryonal fibronectin to target cytokines to the tumour site.97 Finally, chimeric antigen receptor (CAR) T cells hold promise but in primary brain tumours have not yet shown striking activity seen in some liquid cancers, primarily because of the lack of suitable highly expressed and tumour-specific antigens.
4. Epidemiological, clinical and pre-clinical studies of allergy and glioma
4.1. Studies of allergy and glioma risk
Several epidemiological studies and meta-analyses reported an approximate 30-40% decreased glioma risk associated with an allergy history (Figure 5A), with stronger findings for high-grade glioma7,98-100. Studies were often based on self-report or self-reported physician-diagnosed allergies, which may be limited by patient or proxy recall biases, temporal variability of allergy symptoms, or reverse causality in retrospective research.101 These studies often took into consideration a history of any allergy and/or specific allergies. In contrast, in some, but not all102, studies based in hospital, health-care, or population-based registries of allergy patients or medication users, there was either no clear association with primary brain or CNS tumours overall (including gliomas)103, or there were positive associations observed.103-105 In one study, inverse associations of self-reported atopy history and glioma varied by ethnicity.106 There were no clear associations between self-reported allergy history and brain tumour risk in recent studies in children and adolescents.107
Figure 5: Allergic inflammation modulation of central nervous system (CNS) homeostasis.