There are also studies of allergy biomarkers, such as total and/or sIgE and glioma. For example, pre-diagnosis concentrations of tIgE were inversely associated with glioma occurrence.108-110 However, regular intake of some types of anti-histamines in allergic populations has been reported to be associated with increased risk of glioma, although this has not been borne out in all studies, a phenomenon that may be dependent on the different types of anti-histamines evaluated.111 Histamine-H4 blocking drugs may moderate CD4+ T-cell functions away from classical allergy-associated Th2 features and support FOXP3+Tregs. 112,113 This could result in reduced production of cytokines such as IL-4, IL-5, IL-13, reduced B-cell class switching to IgE, which together would otherwise support inflammation and surveillance including to the CNS and against glioma.108,114,115 Consistent with this possibility are studies reporting key roles for IL-4 and activated eosinophils in glioma suppression, and systemic treatment with IL-4 transduced glioma cells engendering anti-tumour immunity against intracranial tumours.116-118 A nested case-control study reported that elevated IL-4 and sIL4RA prior to diagnosis was associated with a reduced glioma and glioblastoma risk, and that early gliomagenesis affects circulating immune function proteins.114 In allergic state robust IL-4 and IL-13 responses could function via T cell help to support class switching of B cells to IgE, something that may be influenced by long-term exposure to some types of antihistamines. In accordance, a meta-analysis reported that increased concentrations of total and respiratory allergen sIgE before tumour diagnosis were inversely associated with glioma risk.119 One study reported significant inverse associations between CCL22 and glioma risk; however CCL22 was not associated with self-reported allergy or IgE.120 Another study reported positive associations of sIL10RB, VEGF, beta-Catenin and CCL22 and glioma risk among the 277 pre-diagnostic cytokines evaluated.121 Collectively, studies may point to a potential contribution of classical Th2 immune features in some level of protective immune surveillance from glioma and CNS tumours.
A range of studies of SNPs of genes related to allergy reported some association with either glioma or glioblastoma risk and outcome.122 Genetic variation of HLA was related to glioblastoma risk in a Korean study.123 A recent GWAS study examined specific molecular subtypes of glioma based on IDH mutation, TERT mutation, and 1p/19q codeletion status.124 There were two new regions associated with specific glioma subtypes including a region in D2HGDH (which is also associated with allergy and asthma) that was associated with IDH-mutant but not IDH-wild-type glioma.124 Mendelian randomization studies of genetically predicted allergic disease or serum tIgE generally reported no clear associations with glioma risk; one study reported a positive association with glioblastoma.125-127 One study reported inverse correlations of the genetic architecture of autoimmune conditions and glioma, with increased activation of acquired immune traits (T-cells, NK-cells, myeloid cells) mediating susceptibility to glioma; however, there was no association of glioma and EC or percentage, or with allergic/atopic traits (asthma, hay fever, eczema) which had lower heritability.128 They suggested that previous findings of protective effects of atopic traits may be driven by environmental factors.
4.2. Studies of allergy and glioma prognosis
Two studies reported better prognosis among glioma patients with a history of allergy; in one of these studies, this was shown to be independent of tumour mutational status (IDH)129,130 Prior history of asthma in patients with glioma was associated with higher mortality risk131, while elevated, versus normal or borderline, serum IgE levels were linked with longer survival. Furthermore, higher rates of positive penicillin skin and higher eosinophil counts were reported in patients with glioma compared with healthy controls.131,132
Elevated serum IgE levels and past history of allergies were less frequent in patients with glioma compared with healthy subjects.82,108,133,134 The levels of plasma IgE were lower and especially in low-grade glioma compared with healthy controls, and increased plasma IgE during treatment correlated with better outcomes.134
Associations between allergy-related cytokines/chemokines and prognosis are generally restricted to gene polymorphisms, including in IL-4Ra and IL -1382,135. Allergy-related IL4R rs1805016 and 1805015 (TT genotypes) were associated with long-term survival in high-grade glioma135 whilst IL-4Rα AA conferred survival advantages in GBM.82 Inverse correlations were reported between specific complement proteins and immunoglobulins in relation to glioma grade.136 Aberrant expression of some allergy-associated (e.g., IL-33)137 or anti-inflammatory cytokines (e.g., IL-10138, TGF-β81), corresponded with poor prognosis. Circulating CCL22 levels were associated with improved glioma survival, but were unrelated to allergy history or post-diagnosis IgE.120
Overexpression of Th2-associated genes corresponding to Th2 cell infiltration in GBM, were linked to worse glioma prognosis, whilst lower Th2-cell infiltration was associated with better prognosis.139 AEC also appears to hold roles in predicting prognosis. Eosinophil-based indices in glioblastoma were altered compared to controls and AEC were higher in groups with more favourable prognosis140, although a separate study found prognostic value of AEC only in low-grade glioma (LGG).141 Eosinophil activation has been positively linked to improved overall survival (OS)142; and increased AEC predicted shorter treatment duration with anti-VEGF antibody and more favourable progression-free survival.143 Accordingly, lower AEC correlated with shorter OS144 and AEC falls rapidly as glioma grade increases.145 Observations for basophils are inconsistent and limited to a few studies.140,146 MC activation was positively linked to OS142, including prognostic MC related genes in predicting survival.147 However, increased infiltrating MCs are detectable in GBM compared to LGG.148
Antihistamine usage was reported to have little impact on survival or prognosis, although further research is required.111 Cancer patients' OS rates suffer when first-line treatment options are restricted because of drug-related hypersensitivity reactions. However, there is little information regarding glioma patients with drug allergies to their initial treatment compared with non-allergic glioma patients. Continuing carboplatin and temozolomide treatment after a hypersensitivity reaction using a drug desensitization protocol is safe and effective.149
Overall, higher IgE levels and past history of allergies were less frequent in patients with glioma, while allergy history, higher serum levels of IgE, certain polymorphisms to IL-4Ra, eosinophils, activated eosinophils and MCs appeared to be linked to more favourable prognosis in patients. Contrastingly, asthma, Th-2 associated cell and mediator genes such as IL-33 were linked to worse clinical outcomes. One limitation lies with the variable allergy assessment method. Further prospective research using additional established and emerging allergy biomarkers are required (Box 2).
4.3. Pre-clinical studies of allergy and glioma
Two recent studies reported that allergic airway inflammation (AAI) could delay the progression of experimental low-150 and high-grade gliomas151. Chatterjee et al. used a genetically engineered mouse model of neurofibromatosis type-1-associated optic pathway gliomas (NF1-OPGs) and showed that experimental asthma induction inhibited glioma formation via reduced expression of the microglia-produced optic glioma mitogen, CCL5. Inhibition of CCL5 synthesis by microglia was mediated through increased T-cell expression of decorin. Decorin inhibited CCL5 production through reduced microglia nuclear factor 'kappa-light-chain-enhancer' of activated B cell (NFκB) signalling.150
Poli et al. demonstrated that AAI delays glioblastoma progression in GL261-bearing mice, increasing survival and providing an alternative preclinical model to study the impact of allergy.151 AAI establishment led to the activation of microglia into pro-inflammatory and antigen-presenting cells, as well as increased infiltration of CD4 T-cells in the TME. In addition, mice with deficient adaptive immunity (RAG1-KO) indicated abrogation of allergic protection effects against glioblastoma.151
These findings suggest an interplay between the local innate immune system, specifically microglia, and the systemic adaptive immune system, particularly T-cell responses, in eradicating cancerous cells that develop in the brain in the context of allergic inflammation.
4. Future Research in AllergoOncology
Opportunities exist for future investigation of allergy and glioma risk, prognosis, and treatment response (Box 2, Figure 6A). More studies using clinically relevant allergy biomarkers and updated sub-classification information on gliomas are needed to define patient phenotypes, endotypes, and genotypes (Figure 6B, Table 2).
Future large-scale prospective studies with comprehensive allergy biomarkers measured over the lifecourse are necessary to examine relevant points in etiology (Figure 6C). Integrating exposome approaches may be particularly valuable.152 The concept of the exposome highlights the critical need for more complete environmental exposure assessment in epidemiological studies, i.e. the broad context of “non-genetic” environmental factors. It complements the genome by providing a comprehensive description of lifelong exposure history.
It is unclear whether the reported inverse associations between allergy and glioma will be confirmed in additional prospective studies and whether they are specific to particular allergic disorders and/or allergens or glioma subtypes. Further understanding will be required to define the most relevant allergy biomarkers during early glioma formation and response to treatment, and for which types of gliomas or subtypes. Harmonizing and pooling data from new and existing studies would enhance the power to explore associations, especially given glioma's rarity. There are also other emerging AllergoOncology biomarkers including deficiency of IgE5 or serum IgG4/IgE ratios153 that may be relevant to monitor in glioma. Existing epidemiological studies are primarily conducted in Europe and North America, necessitating research in diverse geographical settings to account for environmental/allergen exposures and population profiles. Future studies are needed to clarify the prognostic role and personalized implications of allergy for patients with glioma. To achieve this, targeted patient cohorts with information on allergy and allergy-related biomarkers are needed to evaluate the prognostic value of different types of allergies and their effect on anti-cancer therapy response. This is especially relevant regarding immunotherapy response or cancer vaccines, exemplified in a recent study reporting that the allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.154
Finally, in-depth understanding of cellular and molecular effects that may be shared between allergic diseases and gliomas is needed. Innovative in-vitro and in-vivo models are needed to further elucidate potential causative molecular mechanisms and stratification in AllergoOncology in relation to glioma (Figure 6D). Understanding the mechanisms of allergic inflammation on brain homeostasis is limited, with few studies investigating the influence of systemic Th2 allergic immune response on CNS dysfunction (Box 1 and Figure 5). Studies indicate that allergy may impact brain homeostasis and induce neuro-inflammation that subsequently could result in a range of neurological effects, including those of relevance for glioma risk and progression. Inflammatory manifestations in the brain during viral infections, such as long COVID, are documented.155 Further studies on the intricate relationship between allergic inflammation and various brain border immune niches is crucial for comprehending the impact of allergies on brain function and may point to potential therapeutic strategies for CNS disorders including glioma. While the synergy between the immune system, the peripheral and CNS is increasingly appreciated as a regulator of both allergic diseases156 and glioma157, the impact of immune cells with regard to the association between both pathologies remains to be explored.
Figure 6: Future research in AllergoOncology