Association of immunoglobulin E levels with glioma risk and survival

INTRODUCTION

Glioma is a primary malignant brain tumor that causes 11,000 cancer-related deaths in the United States each year^1,2. IDH-wildtype glioblastoma (IDH-WT GBM), the most common subtype, carries a median overall survival of 14 months³. GBM has a clear sex bias, where males are more likely to develop glioma and have poorer outcomes than females⁴. In the last two decades, epidemiologic studies have highlighted a putative role of immune-related factors, including viral infections^5,6, allergic conditions⁷ and autoimmune disorders⁸ in gliomagenesis.

A history of allergies is generally associated with a 20% to 40% decrease in the risk of developing glioma^9–12. Using serum immunoglobulin E (IgE) concentrations as a biomarker for allergic sensitization, recent studies have reported an inverse association between elevated IgE levels and glioma risk, where banked serum studies show that this association exists up to 20 years prior to cancer diagnosis^{10,11,13–15}. The association is consistently more robust among females, especially for respiratory IgE and GBM^13,15. In a small cohort of GBM patients, elevated IgE levels have previously been associated with improved survival¹⁶, suggesting that IgE-mediated immune responses may not only suppress tumor development but also slow cancer progression in the tumor microenvironment. Based on these observations, we hypothesized that the relationship between IgE levels and survival may be modified by sex, tumor subtype and IgE class.

In this study, we aimed to refine the relationship between IgE levels and glioma risk according to contemporary molecular classifications and analyze the impact of sex, tumor subtype and IgE class on the association between IgE levels and survival in adult glioma patients.

METHODS

RESULTS

DISCUSSION

We found that elevated levels of total IgE were associated with reduced risk of both IDH-WT and IDH-MT glioma, recapitulating the results of several previous studies^10,11,13,14. In survival analyses, we demonstrated that elevated post-diagnosis serum IgE levels were associated with improved outcomes among patients with IDH-WT tumors. We identified a strong protective effect in IDH-WT female patients, where respiratory IgE seropositivity was associated with a 25% reduction in mortality risk resulting in approximately 7 months of additional survival time. This substantial improvement in median survival rivals the benefit of the principal glioma therapeutic, temozolomide²². Similarly, we observed a higher PAF for positive respiratory IgE than either chemotherapy or surgery in females with IDH-WT glioma. Together, these results highlight substantial differences in immune factors relating to both subtype-specific and sex-specific glioma prognosis.

The mechanism underlying the link between IgE-mediated atopic disease and glioma susceptibility remains unclear. The current prevailing hypothesis is that atopy induces a state of enhanced natural immunosurveillance, which promotes the detection and removal of malignant cells^23,24. Though best known for its roles in allergy and protection against parasitic infections, IgE has been shown to exhibit both direct and cell-mediated effects against tumor cells²⁴. These effects include the reprogramming of immunosuppressive tumor-associated macrophages and the activation of antibody-mediated tumor cell cytotoxicity and phagocytosis. For instance, in murine tumor models, the administration of IgE antibodies has been shown to recruit and re-educate immunosuppressive tumor-associated macrophages toward a tumoricidal phenotype via a TNFα/MCP-1 cascade^25,26. The association between elevated IgE and improved IDH-WT prognosis suggests that some of these IgE-mediated immune responses may have direct antitumor activity within the central nervous system (CNS). Recent research has shown that allergic airway inflammation can induce a pro-inflammatory-like state in microglia that reduced tumor growth in mice models^27,28. Additionally, previous studies have shown that patients with hyper IgE syndrome (HIES) commonly develop white matter hyperintensities in the cerebral hemispheres²⁹, suggesting that IgE-mediated autoimmunity is active in the CNS. Intriguingly, some forms of HIES have been shown to arise from dominant negative mutations in the signaling transduction and activator of transcription 3 (STAT3) gene³⁰, which has been linked to many cancers including glioma^31,32. While the role of STAT3 and the JAK/STAT pathway has been well studied in IDH-WT GBMs^33–35, its significance in IDH-MT glioma is less clear. Further research is needed to investigate the etiologic role of IgE in gliomagenesis, its interaction with genomic alterations and its potential as a therapeutic intervention.

While sex-specific differences in respiratory IgE and GBM risk have been previously reported^13,15, this study is the first to suggest sexual dimorphism in the link between IgE and GBM survival. It is well established that males and females exhibit distinct immunological responses to foreign and self-antigens, which contribute to differences in susceptibility to autoimmune diseases, malignancies and allergies³⁶. While adolescent males tend to be more affected by allergies and have higher allergen-specific IgE sensitization than females, rates of atopy and allergic disease in females increase during puberty to levels comparable to that in males^37–39. Although the mechanisms by which sex hormones modulate allergy-induced inflammation are complex, experimental studies suggest that estrogen enhances immunological recall responses while testosterone dampens such responses^36,40. Estrogen is thought to promote a Th2 cell bias^36,41, which may enhance allergic inflammation and promote direct anti-GBM activity via IgE antibody dependent cellular cytotoxicity (ADCC)⁴². Intriguingly, in female patients with IDH-MT glioma, positive respiratory IgE appeared to increase mortality risk, although the association did not achieve statistical significance. This finding should be interpreted with caution and further replicated, but it suggests the possibility of female sex hormones interacting with tumor-specific immune features to modify the association between IgE and overall survival. Functional studies are needed to elucidate possible mechanisms by which the differential expression of sex hormones between males and females influences IgE-related immune responses against glioma.

Although we observed improved survival among IDH-WT patients with positive respiratory IgE, elevated food IgE was not associated with mortality risk. Isolated associations between respiratory IgE levels and glioma risk were observed in two previous studies^13,15, suggesting that the effect of respiratory IgE may reflect the mechanism by which allergic inflammation influence glioma development and progression. It may be that specific respiratory allergens share epitopes with tumor antigens, such that adaptive immune cells primed by respiratory allergens recognize glioma cells more efficiently and have stronger antitumor effects. However, this hypothesis fails to account for previous reports of an inverse association between contact allergy, a delayed-type hypersensitivity reaction of the skin, and brain cancer^9,43, which broadly indicate that the antitumor activity of allergic inflammation may not be linked to specific allergens or IgE itself. Furthermore, we observed a reduction in glioma risk in patients with either positive respiratory IgE or positive food IgE, suggesting that IgE-related effects on gliomagenesis are potentially independent of the class of IgE antibodies. Elevated food IgE was less common than respiratory IgE (6% vs. 41%); therefore, our study may lack statistical power to detect an association with mortality.

In addition to small sample sizes in some stratified analyses, our study has several limitations. Our cohort was initially categorized using WHO 2016 criteria and lacks some somatic mutations necessary for WHO 2021 classification. Nevertheless, IDH mutation captures the most prognostically significant glioma feature. Blood samples used to measure IgE antibody levels were collected a median of 95 days post-surgery among cases and may be influenced by the immunosuppressive effects of glioma treatment or the tumor itself. While there is some potential for this to confound the protective effect of IgE on glioma susceptibility, plasma IgE levels collected as much as 20 years before diagnosis have been reported to be associated with glioma risk^13,14. Furthermore, in our analyses, adjustment for dexamethasone use did not substantively alter the effect of IgE levels on survival. Although use of dexamethasone and temozolomide were well documented in our cohort, we did not have information on the use of other immunomodulatory medications that have been associated with glioma risk among individuals with a history of allergies .

In this study we replicated the established association between elevated serum IgE and reduced glioma risk in the largest cohort to date. We also discovered that elevated IgE is associated with improved survival, especially in females, where the population attributable fraction to survival time was greater than the effects of treatment. These analyses were rigorously adjusted for potential imbalance in baseline covariates between IgE groups using an IPTW approach²⁰, which can provide less biased and more precise estimates than multivariable regression in highly stratified analyses with few events per confounder⁴⁵. Age, sex, and race/ethnicity have been consistently associated with measured IgE levels and glioma risk. As such, we felt it essential to balance these strong confounders between IgE groups to best assess the direct implications of IgE antibody levels on glioma risk and survival in our observational data. Taken together with known sex differences in immune responses, these results suggest that IgE-related immunologic features may contribute to both the higher risk of glioma in males and the female survival advantage observed among GBM patients. Our results provide support for further investigations including functional studies to assess the therapeutic potential of IgE-based immunotherapies for GBM.

Supplementary Material

Data Availability Statement:

All data from this study are a part of the University of California, San Francisco Adult Glioma Study and are available upon request from dbGap (accession phs001497.v2.p1).