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\begin{document}

\title{AllergoOncology: Biomarkers and Refined Classification for Research in
the Allergy and Glioma Nexus - a Joint EAACI-EANO Position Paper}



\author[1]{Michelle Turner}%
\author[2]{Urszula Radzikowska}%
\author[3]{Denisa Ferastraoaru}%
\author[4]{Mariona Pascal}%
\author[5]{Pieter Wesseling}%
\author[6]{Alex McCraw}%
\author[7]{Claudine Backes}%
\author[6]{Heather Bax}%
\author[8]{Christoph Bergmann}%
\author[9]{Rodolfo Bianchini}%
\author[10]{Luigi Cari}%
\author[11]{Leticia De las Vecillas}%
\author[12]{Elena Izquierdo}%
\author[7]{Frida Lind-Holm Mogensen}%
\author[7]{Alessandro Michelucci}%
\author[7]{Petr V. Nazarov}%
\author[7]{Simone P. Niclou}%
\author[10]{Giuseppe Nocentini}%
\author[13]{Markus Ollert}%
\author[14]{Matthias Preusser}%
\author[14]{Nataliya Rohr-Udilova}%
\author[7]{Andrea Scafidi}%
\author[7]{Reka Toth}%
\author[15]{Mieke Van Hemelrijck}%
\author[16]{Michael Weller}%
\author[17]{Uta Jappe}%
\author[12]{Maria Escribese}%
\author[9]{Erika Jensen-Jarolim}%
\author[6]{Sophia Karagiannis}%
\author[7]{Aurelie Poli}%
\affil[1]{Fundacion Privada Instituto de Salud Global Barcelona}%
\affil[2]{Universitat Zurich Schweizerisches Institut fur Allergie- und Asthmaforschung}%
\affil[3]{Montefiore Medical Center}%
\affil[4]{Hospital Clinic de Barcelona Centre de Diagnostic Biomedic}%
\affil[5]{Amsterdam UMC Locatie VUmc Afdeling Pathologie}%
\affil[6]{King's College London School of Basic \& Medical Biosciences}%
\affil[7]{Luxembourg Institute of Health}%
\affil[8]{RKM740 Interdisciplinary Clinics}%
\affil[9]{Medizinische Universitat Wien Zentrum fur Pathophysiologie Infektiologie und Immunologie}%
\affil[10]{Universita degli Studi di Perugia Dipartimento di Medicina e Chirurgia}%
\affil[11]{Instituto de Investigacion Hospital Universitario La Paz}%
\affil[12]{Universidad CEU San Pablo Facultad de Medicina}%
\affil[13]{Luxembourg Institute of Health Department of Infection and Immunity}%
\affil[14]{Medical University of Vienna}%
\affil[15]{King's College London School of Cancer \& Pharmaceutical Sciences}%
\affil[16]{UniversitatsSpital Zurich Neurologische Klinik}%
\affil[17]{Forschungszentrum Borstel Leibniz Lungenzentrum}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Epidemiological studies have explored the relationship between allergic
diseases and cancer risk or prognosis in AllergoOncology. Some studies
suggest an inverse association, but uncertainties remain, including in
IgE-mediated diseases and glioma. Allergic disease stems from a
Th2-biased immune response to allergens in predisposed atopic
individuals. Allergic disorders vary in phenotype, genotype, and
endotype, affecting their pathophysiology. Beyond clinical manifestation
and commonly used clinical markers, there is ongoing research to
identify novel biomarkers for allergy diagnosis, monitoring, severity
assessment, and treatment. Gliomas, the most common and diverse brain
tumours, have in parallel undergone changes in classification over time,
with specific molecular biomarkers defining glioma subtypes. Gliomas
exhibit a complex tumour-immune interphase and distinct immune
microenvironment features. Immunotherapy and targeted therapy hold
promise for primary brain tumour treatment, but require more specific
and effective approaches. Animal studies indicate allergic airway
inflammation may delay glioma progression. This collaborative European
Academy of Allergy and Clinical Immunology (EAACI) and European
Association of Neuro-Oncology (EANO) Position Paper summarizes recent
advances and emerging biomarkers for refined allergy and adult-type
diffuse glioma classification to inform future epidemiological and
clinical studies. Future research is needed to enhance our understanding
of immune-glioma interactions to ultimately improve patient prognosis
and survival.%
\end{abstract}%



\sloppy




\textbf{Corresponding author}: Aur\selectlanguage{ngerman}élie Poli; Neuro-Immunology Group,
Department of Cancer Research, Luxembourg Institute of Health,
Luxembourg, Luxembourg. Aurelie.poli@lih.lu

\textbf{Conflict of interest statement:}

All authors have read and approved the Position Paper.

AMC, AM, AP, AS, ClB, DF; FLM, EI, GN, LC, LV, MCT, MPa, MO, MVH, MW,
NRU, SPN, PVN, PW, RT, RB and UR declare no conflict of interest.~

ChB received honoraria for presentations from Allergy Therapeutics,
Bencard, HAL Allergy and SCS. EJJ declares inventorship in patents on
allergen immunotherapy formulation with Biomedical International R+D,
Vienna, Austria, of which she is a shareholder. She received honoraria
for presentations from Allergy Therapeutics, AllergoPharma, Bencard,
Meda, Roxall, ThermoFisher, and consulted previously for MediGene,
Germany, Novartis, for Allergy Therapeutics and Dr. Schär. HJB is
employed through a fund provided by Epsilogen Ltd. (formerly IGEM
Therapeutics Ltd.) and holds patents on anti-tumor IgE antibodies. MME
has received honoraria from lectures from the following companies:
Stallegenes Greer, Diater and GSK. MPr has received honoraria for
lectures, consultation or advisory board participation from the
following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis,
Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma,
Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead,
Daiichi Sankyo, Sanofi, Merck Sharp \& Dome, Tocagen, Adastra, Gan \&
Lee Pharmaceuticals, Servier. SNK is founder and shareholder of
Epsilogen Ltd. (formerly IGEM Therapeutics Ltd.) and has received funds
from IGEM Therapeutics Ltd/Epsilogen Ltd. HJB is employed through a fund
provided by Epsilogen Ltd.~SNK and HJB are inventors of patents on
antibody technologies. AJM is supported by the UK Medical Research
Council (MR/R015643/1) and King's College London member of the MRC
Doctoral Training Partnership in Biomedical Sciences.~UJ has received a
hotel accommodation and catering for a lecture and chairing of a
workshop organized by ALK Abello. The honorarium went to her
institution, the RCB. Her research on molecular allergology is funded by
the Federal Ministry of Education and Science, the Federal Ministries of
Technology, Economy and Technology, Food and Agriculture (BMEL), the
German Research Foundation, and the Kanert Foundation. MW has received
research grants from Quercis and Versameb, and honoraria for lectures or
advisory board participation or consulting from Bayer, Curevac, Medac,
Novartis, Novocure, Orbus, Philogen, Roche and Sandoz.

\textbf{Funding and support:}

The Task Force named ``AllergoOncology in the Era of Personalized,
Stratified and Precision Medicine'' (STRATALLON) was supported by the
European Academy for Allergy and Clinical Immunology (EAACI). The
authors would like to thank EAACI for its financial support in the
development of this Position Paper. The writing of this Position Paper
was undertaken by representatives from EAACI and the European
Association of Neuro-Oncology (EANO), who collaborated under a
Memorandum of Understanding.

AP/AS is financially supported by the Action Lions Vaincre le Cancer
association. AP is supported by FNRS-Télévie (PDR-TLV 2023 RESTAGE). FLM
is supported by the Luxembourg National Research Fund (FNR) through the
FNR-PRIDE program i2TRON for doctoral education (PRIDE/14254520/I2TRON).
MCT is funded by a Ramón y Cajal fellowship (RYC-2017-01892) from the
Spanish Ministry of Science, Innovation and Universities and co-funded
by the European Social Fund. ISGlobal acknowledges support from the
grant CEX2018-000806-S funded by MCIN/AEI/ 10.13039/501100011033, and
support from the Generalitat de Catalunya through the CERCA Program. MME
has projects funded by Fundación Mutua Madrileña, Grant/ Award Number:
AP177712021; Ministerio de Ciencia, Innovación y Universidades,
Grant/Award Number: PCI2018-092930; Instituto de Salud Carlos
III-European Regional Development Fund, Grant/Award Number: RD16/0
006/0015,RD21/0002/0008. SNK has projects supported by the National
Institute for Health and Care Research (NIHR) Biomedical Research Centre
(BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's
College London (IS-BRC-1215-20006); the Medical Research Council
(MR/L023091/1, MR/V049445/1, MR/R015643/1), the Biotechnology and
Biological Sciences Research Council (BB/T008709/1); Breast Cancer Now
(147; KCL-BCN-Q3); the Cancer Research UK King's Health Partners Centre
at King's College London (C604/A25135); The Guy's and St Thomas's
Foundation Trust Charity (Melanoma Special Fund, 573); Innovate UK
(463087) the British Skin Foundation; Cancer Research UK (C30122/A11527;
C30122/A15774). UJ has projects funded by the German Research Foundation
(DFG) (JA 1007/2-3), the Federal Ministry of Education and Science
(BMBF) (DZL and INDICATE-FH), and the Federal Ministry of Food and
Agriculture (BMEL) (AptaSens).

\textbf{Contribution statement:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{SECTIONS}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{CONTRIBUTORS}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{MAIN TEXT{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Abstract}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, MCT, SK, EJJ, PW\textbf{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{1. Introduction}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, MCT, UR, LC, GN, SK\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{2. Allergy: Current and emerging biomarkers, and therapeutic
approaches{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, MME, UR, UJ, DEF, MPa ,EI, SK, LV, EJJ\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.1. Immune dysregulation\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
DEF, UJ, MPa\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.2. Current and emerging biomarkers in the diagnosis and
treatment\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
UJ, MME, UR, EI, LV, DEF, Mpa, EJJ\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.2.1. Clinically-used biomarkers\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.2.2. Emerging cellular markers\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.2.3. Emerging type-2 cytokines and proteins\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.2.4. Emerging genetic and molecular omics markers\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
MME, UR, UJ\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
2.3.Therapeutic approaches\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
ChB, UJ, MPa, LV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{3. Glioma: Updated classification, immune biomarkers, and
therapeutic approaches}{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
PW\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.1. Diagnosis and classification{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
PW, AP{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2. Immune response and biomarkers{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
MPr, SN\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.3. Immune-therapeutic approaches\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
MW\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{4. Epidemiological, clinical and pre-clinical studies of allergy
and glioma{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
MCT, AMC, AP, SK\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4.1. Studies of allergy and glioma risk{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
MCT, AMC, AP, SK\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4.2. Studies of allergy and glioma prognosis\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AMC, AP, SK, MCT\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
4.3 Pre-clinical studies of allergy and glioma{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{5. Future research in AllergoOncology{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
All authors\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{6. Conclusion}{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
All authors\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{REFERENCES{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{FIGURES{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 1:} Proposed hypotheses of associations between allergic
disorders and cancer development and progression within the concept of
immunosurveillance and immunoediting.{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, NRU\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 2:} Overview of allergic inflammation: cellular and
molecular mechanisms{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 3:} WHO classification of gliomas over time\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
PW, RT\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 4:} The border-associated immune compartments of the
brain\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, FLH\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 5:} Allergic inflammation modulation of central nervous
system (CNS) homeostasis.{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP{}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Figure 6:} Future research in AllergoOncology\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{BOXES{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Box 1:} Allergic inflammation and brain physiology\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, FLH\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Box 2:} Research questions for new studies in allergy and glioma
risk, prognosis, and treatment{}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP, MCT, EJJ, SNK\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{TABLES{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Table 1:} Selected biomarkers and individual demographics to
study links between allergic diseases and gliomas\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
All\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Table 2:} Biological drugs targeting molecules relevant for
atopic / allergic disease pathomechanisms\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
UJ, ChB\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{SUPPLEMENTARY MATERIALS{}}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{METHODS}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{SUPPLEMENTARY TABLE 1:} WHO classification of gliomas in 2007
(4\textsuperscript{\textbf{th}} edition), 2016 (revised
4\textsuperscript{\textbf{th}} edition) and 2021
(5\textsuperscript{\textbf{th}} edition)\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
PW\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Short title}:

Stratifying AllergoOncology Research in Glioma

\textbf{Key words}: Atopy, Brain cancer, Epidemiology, IgE,
NeuroImmunology

\textbf{Abbreviations:}

AAI: Allergic airway inflammation

AEC: Absolute eosinophil count

AD: Atopic dermatitis

AIT: Allergen-specific immunotherapy

AR: Allergic rhinitis

BBB: Blood brain barrier

BRAF: B-raf proto-oncogene

CCL11: Eotaxins

CCL22: CC-chemokine ligand-22

CDKN2A/B: Cyclin-dependent kinase inhibitor 2A/B

CNS: Central nervous system

CSF: Cerebrospinal fluid

CSF-1: Colony stimulating factor 1

DHR: Drug hypersensitivity reactions

EGFR: Epithelial growth factor receptor

EoE: Eosinophilic esophagitis

FeNO: Fractional excretion of nitric oxide

FLG: Filaggrin

ICS: Inhaled corticosteroids

IDH1/2: Isocitrate dehydrogenase gene 1/2

ILC2: Type-2-innate lymphoid cells

LGG: Low grade glioma

LTB4: Leukotriene B4

MAT: Mast cell activation tests

MCs: Mast Cells

MGMT: O6-methylguanine DNA methyltransferase

miRNAs: MicroRNAs

MRGPRX2: MAS-related G protein-coupled receptor-X2

NF\selectlanguage{greek}κ\selectlanguage{english}B: Nuclear factor `kappa-light-chain-enhancer' of activated B cell

NTRK~: Neurotrophic tyrosine receptor kinase

OIT: Oral immunotherapy

ORMDL3: ORMDL sphingolipid biosynthesis regulator 3

PD-1/PD-L1: Programmed cell death (PD)-1 / PD ligand 1

pMAT: Passive MC activation testing

RCTs: Randomized controlled trials

sIgE: Allergen-specific IgE

SLC40A1: Solute carrier family-40 member-1

SNP: Single nucleotide polymorphism

T2: Type-2

TERT: Telomerase reverse transcriptase

TGF-b: Transforming growth factor beta

tIgE: Total serum IgE

TSLP: Thymic stromal lymphopoietin

VEGF: Vascular endothelial growth factor

\textbf{1.~~~ Introduction}{}

Numerous epidemiological studies have investigated associations between
a history of allergic diseases and cancer risk or prognosis contributing
to progress in the field of AllergoOncology.\textsuperscript{1-5}
Notably, investigations have revealed findings of inverse associations
between allergies and cancer risk, in particular for
glioma.\textsuperscript{6} However, despite these findings, there remain
outstanding questions and research gaps for IgE-mediated diseases and
cancer, including glioma.\textsuperscript{7,8}{}

Allergic diseases and cancer are both influenced by genetic and
environmental factors, with potential impacts of allergic inflammation
in cancer depending on the tumour subtype and its microenvironment.
Several hypotheses have been proposed to define this complex interplay,
with pro- and anti-tumoral outcomes integrated into the ``combinatorial
hypothesis''.\textsuperscript{8} In the cancer initiation phase, the
``prophylaxis hypothesis'' suggests that allergic symptoms may decrease
tumour risk by expelling environmental carcinogens and stimulating
behavioural avoidance. The ``immunosurveillance hypothesis'' defines
atopy as general enhanced immune responsiveness. The ``chronic
inflammation hypothesis'' proposes that allergic inflammation, oxidative
damage, and subsequent gene mutations, increase neoplastic cell risk.
Finally, the ``Th2-skewing hypothesis'' argues that type-2 (T2) immune
response dominance in allergic disorders potentiates a pro-tumoral
microenvironment over anti-tumoral Th1-immunity \textbf{(Figure
1)}.\textsuperscript{8}

\textbf{\emph{Figure 1: Proposed hypotheses of associations between
allergic disorders and cancer development and progression within the
concept of immunosurveillance and immunoediting.}}

\textbf{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Turner-et-al--Figure-11/Turner-et-al--Figure-11}
\caption{{This is a caption
{\label{474644}}%
}}
\end{center}
\end{figure}

\selectlanguage{ngerman}\emph{Tumour development involves processes from initiation through
progression. Immunogenic transformed cells trigger immune responses,
leading to cancer cell elimination via innate and adaptive immunity.
This dynamic process generates antigen-specific anti-tumour immunity
maintaining dormancy. However, immunoediting and cancer progression can
develop poorly immunogenic cells escaping immune surveillance.
Hypotheses address the link between allergies and cancers:
``prophylaxis'' suggests allergic symptoms reduce risk via carcinogen
expulsion, ``chronic inflammation'' proposes inflammation-driven
mutations, ``immunosurveillance'' defines atopy as enhanced immune
responsiveness, and ``Th2 skewing'' argues allergic Th2 dominance
promotes a pro-tumoral environment.Abb. Breg: Regulatory B cells; DC:
Dendritic Cells; Eos: Eosinophils; ILC: Innate Lymphoid cells; Macro:
Macrophage; NK: Natural Killer cells; Treg: Regulatory T-cells.
Illustration created with «~BioRender.com».}

\par\null

Recent developments in biomedicine techniques allow the integration of
omics and non-omics data and have revealed molecular heterogeneity in
allergic disorders and glioma, with specific molecular subtypes related
to disease severity, prognosis, and treatment
options.\textsuperscript{9-12} There are a range of phenotypes and
endotypes for allergic diseases, such as allergic and non-allergic
asthma or rhinitis. Advancing neuropathological, cellular, and molecular
approaches, including DNA aberrations and methylation profiles, have
revealed heterogeneity in glioma classification.\textsuperscript{10}
Adopting up-to-date molecular and genetic sub-classification approaches
is relevant for research in AllergoOncology to further improve
understanding of immune-glioma interactions.

In this Position Paper, members of the European Academy of Allergy \&
Clinical Immunology (EACCI) and the European Association of
Neuro-Oncology (EANO) jointly provide an overview of strategies for
defining allergic diseases and adult-type diffuse gliomas. The paper
summarizes biomarkers for diagnosing and managing both conditions. It
provides a narrative review of the epidemiological and pre-clinical
evidence on associations between allergy and glioma. Additionally, the
paper outlines how emerging allergy biomarkers can be utilized in
next-generation AllergoOncology studies to enhance understanding of the
aetiology and clinical management of glioma patients.

\textbf{2.~~~ Allergy: Current and emerging biomarkers and therapeutic
approaches}

\textbf{2.1.~} \textbf{Immune dysregulation}

Allergic disease results from a Th2-biased immune response to
environmental allergens in genetically predisposed atopic individuals.
Trained immunity, characterized by innate immune cells displaying
heightened reactivity and memory-like characteristics which occurs
through transcriptomic, epigenetic, and metabolic reprograming following
exposure to specific triggers, may play an important role in this
context.\textsuperscript{13} Airway epithelium repetitively primed with
Th1 (IFN-g) or Th2 (IL-4) cytokines present imprinted, polarized
``Th1/Th2'' gene networks. Human bronchial epithelial cells stimulated
with IL-4, but not IFN-g, produced enhanced levels of IL-24. IL-24 was
also increased in allergic rhinitis patients, demonstrating its
potential as a biomarker of T2-polarized epithelium and allergic
inflammation.\textsuperscript{14} Additionally, damaged epithelial
barriers result in sensitization to different allergens due to alarmins
that mature CD4\textsuperscript{+}T-cells into Th2-cells and stimulate
the overproduction of IL-4, IL-5, IL-9, IL-13 and IL-31. These cytokines
promote the Th2-immune response, resulting in IgE isotype switching and
involve mechanisms in chronic tissue remodelling during allergic
conditions. These include mucus hypersecretion, vascular leakage, smooth
muscle cell hypercontraction, neurogenesis, and
angiogenesis.\textsuperscript{15,16} During sensitization, IgE binds to
Fc\selectlanguage{english}eRI on mast cells (MCs) and basophils. Upon allergen exposure, the
IgE-bound receptors aggregate, triggering immediate hypersensitivity
reactions with various clinical manifestations affecting single or
multiple organs with mild-moderate to severe symptoms including
anaphylaxis \textbf{(Figure 2)}.\textsuperscript{15,16} \textbf{}
Allergic disorders are heterogeneous, with distinct phenotypes,
genotypes and endotypes that differ in pathophysiology \textbf{(Table
1).}\textsuperscript{12}

\textbf{\emph{Figure 2: Overview of allergic inflammation: cellular and
molecular mechanisms}}

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Turner-et-al--Figure-2/Turner-et-al--Figure-2}
\caption{{This is a caption
{\label{543468}}%
}}
\end{center}
\end{figure}

\emph{The allergic response consists of two distinct phases. In the
early phase or} \textbf{\emph{sensitization phase}}\emph{, initial
sensitization to an allergen released from an allergen source (brownish
spheres) and memory activation to the molecular allergen occur, while in
the later phase or} \textbf{\emph{effector phase}}\selectlanguage{ngerman}\emph{, a response is
triggered upon re-exposure to the allergen. During the immediate
reaction this leads to the release of inflammatory mediators due to the
cross-linking of allergen-bound specific IgE on basophils, mast cells
and eosinophils. Then, during the late reaction, after re-exposure to
allergen specific T-helper cells (Th-2 and Th17) further increase local
inflammation leading to tissue remodelling and chronicity. ~Abb. B: B
cells; DC: Dendritic Cells; ILC: Innate Lymphoid cells, Th: T-helper
cells. Illustration created with «~BioRender.com».}

\par\null

\textbf{2.2.~} \textbf{Current and emerging biomarkers in diagnosis and
treatment} \textbf{{}}

\textbf{2.2.1.~~~} \textbf{Clinically-used biomarkers}

Allergy diagnosis relies on evaluating the history of allergen exposure,
symptomatology, and tests to determine sensitization. Elevated total
serum IgE (tIgE) is associated with allergic disease, parasitosis and
specific immunologic abnormalities. It has traditionally been used as a
marker for atopy/allergy, prompting further evaluation.

Allergen-specific IgE (sIgE) is detected on MCs (skin prick testing) and
in serum. sIgE can be detected against whole extracts as well as
components obtained recombinantly or purified/native. Identifying
cross-reactivity and primary sensitization aids treatment decisions such
as allergen-specific immunotherapy (AIT).\textsuperscript{17} The
glycosylation patterns of sIgE (and sIgG) have biomarker potential
regarding allergy diagnosis, severity and treatment efficacy (tolerance
induction). Sequential epitope-specific IgE-profiling appears valuable
in peanut oral immunotherapy (OIT)\textsuperscript{18}. Lower sIgE to
food allergens at baseline was related to increased efficacy of peanut
OIT.\textsuperscript{19} Allergen provocation testing is the gold
standard when clinical history is inconclusive.\textsuperscript{20}{}

Indirect sIgE-detection can be performed with a flow-cytometry-based
functional assay that measures basophil activation after allergen
exposure (basophil activation test, BAT). This test discriminates
between sensitization and allergy for peanut and red meat
allergies.\textsuperscript{21-23} The value of BAT extends to diagnosing
various conditions, such as drug hypersensitivity, encompassing cases
like IgE-based anti-tumour therapy in cancer
patients\textsuperscript{24}, as well as allergies to hymenoptera
venom.\textsuperscript{21} BAT has been optimized for broader
use.\textsuperscript{21} Passive MC activation testing (pMAT) can
provide additional information, for example, when basophils are
non-responsive to allergens. Ratio analysis of sIgE to tIgE can aid in
clinical interpretation.\textsuperscript{25}{}

Serum tryptase is a biomarker for anaphylaxis. Tryptase is released by
activated MCs in 30 min to 2h. Elevated tryptase in the acute phase
confirms the diagnosis, but normal levels do not exclude
anaphylaxis.\textsuperscript{26,27} Basal serum tryptase is also
increased in certain MC disorders.

Eosinophilia, or elevated absolute eosinophil count (AEC), is found in
atopy, T2-high asthma, atopic dermatitis (AD), eosinophilic
gastrointestinal disorders and delayed drug hypersensitivity reactions
(DHR), although it is not specific. Eosinophilia is also observed in
parasitic infections and autoimmune diseases. T2-high asthma includes,
among others, allergic and eosinophilic asthma pheno-endotypes. Allergic
asthma is characterized by increased circulating allergen-specific IgE,
while eosinophilic asthma can be diagnosed based on increased blood
(\textgreater{}300/uL) or sputum eosinophil numbers (³3\%). On the other
hand, T2-low asthma, including neutrophilic or paucigranulocytic asthma
is characterized by low IgE, AEC, and allergic
symptoms.\textsuperscript{28} These phenotypes have different severity
and treatment implications in adults and
children.\textsuperscript{15,29} AEC predicts therapeutic response to
biologics in severe asthma (e.g., anti\selectlanguage{english}-IL\selectlanguage{english}-5).\textsuperscript{30,31}{}

Fractional excretion of nitric oxide (FeNO) is a reproducible and
non-invasive indirect biomarker of IL-13-mediated T2-airway
inflammation. Higher values of FeNO are found in T2-high compared with
T2-low asthma and help confirm diagnosis in adults and children. It
predicts response to inhaled corticosteroids (ICS).\textsuperscript{32}
Elevated FeNO values during ICS therapy do not support ICS dose
reduction. Low FeNO values alone do not exclude bronchial asthma. FeNO
levels vary with different asthma biologics.\textsuperscript{33}{}

\textbf{2.2.2.~~~} \textbf{Emerging cellular markers{}}

Allergen-specific Th2A-cells, found in allergic individuals, are
CD4\textsuperscript{+}CRTH2\textsuperscript{+}CD161\textsuperscript{high}HPGDS\textsuperscript{+}CD27\textsuperscript{low}CD49d\textsuperscript{high}ST2\textsuperscript{high}
memory cells that play a pathogenic role in AD, food allergy, asthma,
and eosinophilic esophagitis (EoE).\textsuperscript{34} Th2A-cell
frequency inversely correlates with treatment efficacy.
CD38\textsuperscript{+}Th2A-cells are an emerging clinical biomarker in
T2-high asthma, with CD38 upregulation in Th2A-cells and downregulation
with immunotherapy treatment.\textsuperscript{35}{}

MCs are activated in allergic diseases like asthma and AD, with
MAS-related G protein-coupled receptor-X2 (MRGPRX2) \emph{} being a new
biomarker for allergic disorders such as asthma and drug allergy. Serum
MRGPRX2 levels are elevated in allergic asthma, especially in those
responding well to ICS.\textsuperscript{36} This receptor is expressed
on cutaneous MCs in patients with severe chronic spontaneous
urticaria.\textsuperscript{37} Some reactions to specific drugs such as
fluoroquinolone antibiotics or neuromuscular blocking agents have been
postulated to be induced by MC MRGPRX2-mediated
mechanisms.\textsuperscript{38} MC activation tests (MAT) are being
developed to aid diagnosis and monitoring of allergic
diseases.\textsuperscript{39} However, MC activation is not always
present, requiring differential diagnosis.

T2-innate lymphoid cells (ILC2) contribute to inflammation in allergic
disorders, such as allergic rhinitis (AR), chronic sinusitis, asthma and
AD, by enhancing the activity of Th2-cells, eosinophils and their
cytokines. ILC2 are increased in the blood, lung and skin of individuals
with these conditions and are related to disease severity and treatment
response.\textsuperscript{40} Notably, allergen-specific immunotherapy
reduced frequencies of sputum ILC2s in patients with grass-pollen
allergic rhinitis and asthma.\textsuperscript{41}{}

\textbf{2.2.3 Emerging} \textbf{type-2 cytokines and proteins}

Allergic patients generally present higher serum T2-cytokine levels
compared to healthy individuals. However, they are not routinely used as
clinical biomarkers in allergy due to usually low serum detectable
levels.\textsuperscript{42} Elevated IL-4 differentiates
\href{https://www.sciencedirect.com/topics/medicine-and-dentistry/allergic-asthma}{T2-high
from T2-low}asthma, while elevated IL-4 and IL-5 distinguishes asthma
persistence in adults and children, respectively. IL-13 and IL-33
correlate with asthma severity, while thymic stromal lymphopoietin
(TSLP) levels are increased in the skin of AD patients and in the
airways of patients with severe asthma. Decreased T2-cytokines are
associated with treatment success.\textsuperscript{42,43}{}

Elevated blood levels of CC-chemokine ligand-22 (CCL22) have been
detected in AD patients compared to controls and are associated with
disease severity.\textsuperscript{42} Eotaxins (CCL11) are proposed
biomarkers for AR, asthma and AD.\textsuperscript{42} Periostin is a
biomarker of T2-inflammation in adults; however, its levels vary in
children until bone growth stops.\textsuperscript{44} Eicosanoids play a
role in allergy pathomechanisms. Levels of leukotriene B4 (LTB4) were
increased in patients with asthma.\textsuperscript{32} Increased
lipocalin-2 after sublingual immunotherapy~was associated with clinical
benefit.\textsuperscript{45} Additionally, prostaglandin E2 (PGE2) was
upregulated in untreated allergic rhinitis and asthma patients with a
significant decrease observed after AIT. Notably, PGE2 levels correlated
with T2-inflammation and clinical markers, such as IL-13, sputum
eosinophil counts and symptom scores.\textsuperscript{41} Lastly,
decorin, an extracellular matrix proteoglycan participates in the
pathogenesis of allergic asthma by reducing bioavailability of
\emph{transforming growth factor beta} \emph{}
(TGF-b).\textsuperscript{46}\textbf{{}}

\textbf{2.2.4 Emerging genetic} \textbf{and molecular omics markers}

Genomic loci, such as 17q21 are associated with allergic diseases. This
region is associated with gene expression of ORMDL sphingolipid
biosynthesis regulator 3 (\emph{ORMDL3}), an inhibitor of \emph{de novo}
sphingolipid synthesis, a mediator in severe allergic
asthma.\textsuperscript{47} \emph{ORMDL3} is expressed in airway smooth
muscle cells, airway epithelium, CD4 T-cells, and eosinophils.
\emph{ORMDL3} expression is related to exaggerated T2-inflammation,
increased expression of adhesion molecule ICAM-1, enhanced glycolysis
and pro-inflammatory cytokine production (IL-6 and IL-18) in both
structural lung cells and infiltrating immune cells in the
lungs.\textsuperscript{48} Filaggrin (FLG) genetic variations are
genetic biomarkers in eosinophilic asthma\textsuperscript{49} and
AD,\textsuperscript{50} related to a higher risk of presenting Th2
multimorbidity.

Polygenic risk scores combining 41 genetic polymorphisms show
significant associations with asthma risk.\textsuperscript{51} HLA-DR1
is abundant in cat allergy, while HLA-DR4 is associated with Alt a 1
responsiveness in \emph{Alternaria} allergy.\textsuperscript{52}
Notably, single nucleotide polymorphism (SNP) on D2HGDH (rs34290285)
demonstrated significance in both asthma and allergic
diseases.\textsuperscript{53} HLA-B alleles are related to drug
hypersensitivity.\textsuperscript{54,55} Forty-two genetic loci are
associated with AR.\textsuperscript{55} MicroRNAs (miRNAs), are small
non-coding RNA molecules involved in gene expression regulation. Several
miRNAs play a role in allergic diseases and have been proposed as
potential biomarkers of both disease pathology and therapy
outcomes.\textsuperscript{56} miR-155 plays a role in AR, AD, and
asthma.\textsuperscript{56} miR-3935, the predicted target of PGE2
receptor (PTGER3), was upregulated during AIT in patients with
allergy.\textsuperscript{41} The detailed role of miRNAs in allergy and
asthma is reviewed elsewhere.\textsuperscript{56}{}

Iron metabolism is involved in childhood allergic asthma. Downregulated
solute carrier family-40 member-1 (SLC40A1) expression correlates with
T2-inflammation in the lung and is used to classify patients into T2-low
and T2-high subgroups. Decreased SLC40A1 results in reduced iron levels
in the airways.\textsuperscript{57}{}

Omics technologies can further explore allergy pathobiology, define
specific endotypes, and refine disease classification and
treatment.\textsuperscript{12}

\textbf{2.3.~} \textbf{Therapeutic approaches}

Antihistamines, decongestants and corticosteroids relieve allergy
symptoms. AIT shifts the Th2-response to a Th1-response, and induces
regulatory T- (Tregs) and B-cells (IL-10\textsuperscript{+} B-cells),
subsequently promoting tolerance to allergens and providing long-term
symptom relief.\textsuperscript{58} AIT is effective across all age
groups, requiring a minimum of 3 years of treatment.\textsuperscript{31}
Randomized controlled trials (RCTs) demonstrated AIT's efficacy in
children (\selectlanguage{english}[?]5 years) and older patients (\textgreater{}65
years).\textsuperscript{59} Individual molecular sensitization profiles
influence AIT effectiveness.\textsuperscript{60} AIT is the only
treatment with maintained efficacy after stopping treatment. AIT can be
combined with biological therapies (treatment antibodies) for
``difficult-to-treat'' allergic asthma or to increase
tolerability.\textsuperscript{61} Biological therapies targeting IgE,
interleukins, IL-receptors or TSLP \textbf{(Table 2)} are used to treat
various allergic disorders.\textsuperscript{30,31} Desensitization
protocols effectively prevent DHR, maintaining first-line treatment when
no equivalent alternatives exist in drug allergy
patients.\textsuperscript{62}{}

\textbf{3. Glioma: Updated classification, immune biomarkers, and
therapeutic approaches}

\textbf{3.1 Diagnosis and classification}

Gliomas are the most common and varied tumours originating from the
central nervous system (CNS) parenchyma. When reviewing the literature
on glioma it is important to acknowledge changes in their classification
(and clinical diagnosis) over time \textbf{(Figure 3)}. Since the 2016
WHO CNS tumour classification (revised 4\textsuperscript{th}
edition)\textsuperscript{63,64}, particular molecular alterations are
part of the definition of multiple gliomas, including adult-type diffuse
gliomas. These latter tumours are characterized by extensive
infiltration of tumour cells in the surrounding CNS parenchyma and
constitute the bulk of adult neuro-oncology practice. The taxonomy of
adult-type diffuse gliomas is now largely based on the presence/absence
of a hotspot mutation in isocitrate dehydrogenase gene 1 or 2 (IDH1 or
IDH2) and of combined, complete loss of the short arm of chromosome 1
and of the long arm of chromosome 19 (1p/19q codeletion). In the 2021 or
5\textsuperscript{th} edition of the WHO CNS tumour
classification\textsuperscript{10} three tumour types are recognized in
this family: diffuse astrocytoma, IDH-mutant (grade 2, 3 or 4);
oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grade 2 or 3); and
glioblastoma, IDH-wildtype, which is not only the most malignant (grade
4), but also the most frequent in adults. Elucidation of molecular
differences between adult- and paediatric-type diffuse gliomas has
allowed for recognizing these as distinct groups of tumours. The 2021
WHO classification now lists (next to adult-type diffuse gliomas) a
family of low-grade and high-grade paediatric-type diffuse gliomas
\textbf{(Supplementary Table 1)}.

\textbf{\emph{Figure 3: WHO classification of gliomas over time.}}\selectlanguage{english}
\begin{figure}[H]
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{\label{261883}}%
}}
\end{center}
\end{figure}

\emph{Sankey plot displaying an overview of how the taxonomy of diffuse
gliomas has changed over time; the size of the strips provides an
indication of the relative frequency of the different tumour types.
Since 2016 molecular characteristics are part of the definition of
multiple gliomas. As a result, (anaplastic) oligoastrocytoma and
gliomatosis cerebri are now generally recognized as another diffuse
glioma type and their diagnosis has almost disappeared. Of note,
different grades of glioma still had their own entry in the 2007 and
2016 classification (e.g., anaplastic astrocytoma = WHO grade III), but
in the 2021 classification grades are assigned within types. Last but
not least, after the introduction of diffuse midline glioma,
H3K27-mutant in 2016, since 2021 more paediatric-type diffuse gliomas
are included as separate tumour types in the classification. For the
sake of clarity only diffuse midline glioma, H3K27-altered and diffuse
hemispheric glioma, H3G34-mutant (both CNS WHO grade 4) are included in
this diagram. The reader is referred to} \textbf{\emph{Supplementary
Table 1}} \emph{for all gliomas as listed in the WHO 2007, 2016 and 2021
classification of CNS tumours, respectively.}

\par\null

In the 2016 classification, only histological features such as mitotic
activity, necrosis, and florid microvascular proliferation were used for
assigning malignancy grade to adult-type diffuse gliomas. More recently,
cIMPACT-NOW presented a compilation of the evidence that particular
molecular characteristics substantially improve the prognostic impact of
grading of these neoplasms.\textsuperscript{65,66} According to the 2021
classification, even in the absence of, for example, microvascular
proliferation and necrosis, an IDH-mutant astrocytoma
with~cyclin-dependent kinase inhibitor 2A/B
\emph{(\emph{CDKN2A}}/\emph{B)}~homozygous deletion is considered as
grade 4. Similarly, in adult patients with a histologically
low(er)-grade, IDH-wildtype diffuse glioma, the presence of one or more
of the following three genetic characteristics is now sufficient for a
diagnosis of glioblastoma, IDH-wildtype (grade 4): telomerase reverse
transcriptase \emph{(TERT}) promoter mutation,~epithelial growth factor
receptor \emph{(EGFR)}~gene amplification, and +7/-10 (i.e., the gain of
whole chromosome~7 and loss of whole chromosome~10).\textsuperscript{10}
These developments in classification necessitated updated guidelines for
the clinical management of patients \textbf{(Table
1)}.\textsuperscript{67}{}

Glioblastoma can be further classified into molecular subtypes,
informing disease progression and clinical practice. ~Wang et al.
identified three subtypes based on molecular features: pro-neural,
mesenchymal, and classical.\textsuperscript{68} Neftel et al. utilized
single-cell RNA-sequencing to identify four cellular states within
glioblastoma\textsuperscript{69}, showing intra-tumoral heterogeneity.
The signatures of individual tumour cells were categorized into
neural-progenitor-like, oligodendrocyte-progenitor-like, astrocyte-like,
and mesenchymal-like.\textsuperscript{68}{}

Although molecular knowledge has enabled more precise clinical
diagnosis, the translation into more effective therapeutic approaches is
lagging behind. Further elucidation of the pathobiology of these tumours
through single-cell expression profiling studies\textsuperscript{70},
longitudinal multiplatform analyses\textsuperscript{71} and of inherited
genetic aspects\textsuperscript{72,73} may be helpful in this
regard.\textsuperscript{74}{}

\textbf{3.2 Immune response and biomarkers}

Gliomas are characterized by a complex immune tumour microenvironment
(TME), with up to 50\% of tumour composition consisting of immune cells
(mainly microglia and glioma-associated macrophages). In much lower
quantities, tumour-infiltrating lymphocytes, monocytes, MCs, eosinophils
and neutrophils are also present.\textsuperscript{75,76} These innate
and adaptive immune cell types directly and indirectly interact with
tumour cells and resident glial cells, neurons and vascular cells. The
immune landscape of gliomas is highly immunosuppressive with
immunologically quiet macrophages and sparse lymphocytic infiltration,
with a shift to Th2.\textsuperscript{77,78} IDH-mutant gliomas display
even less lymphocytes than IDH-wildtype tumors.\textsuperscript{79} The
complex dynamic interplay of the various cell types involves the
expression of a multitude of immunoregulatory factors, partly with
tumour-promoting features, such as cytokines and chemokines (e.g. IL-4,
IL-10, \selectlanguage{greek}\emph{TGF-\emph{β}}\selectlanguage{english}), colony stimulating factor 1 (CSF-1),
immune-checkpoint molecules (e.g. programmed cell death (PD)-1 / PD
ligand 1 (PD-L1) dependent signalling, CD39) among
others.\textsuperscript{75,80} The inflammatory cytokine profile of
glioblastoma (diagnosed via histopathological features) is a valuable
prognostic indicator, with increased levels of immunosuppressive
molecules such as TGF-\selectlanguage{greek}β \selectlanguage{english}related to decreased
survival.\textsuperscript{81} Genotypes of Th2-related IL-4Ra and IL-13
have also been related to prognosis.\textsuperscript{82}{}

Angiogenic (vascular endothelial growth factor (VEGF)), metabolic (e.g.
IDO, ARG1) and dietary factors\textsuperscript{83} influence the
inflammatory microenvironment and immunogenicity of glial brain tumours.
Presumably, the local immune reaction in gliomas is connected to the
systemic immune system via meningeal lymphatic vessels and lymphatic CNS
drainage to cervical lymph nodes\textsuperscript{84-87} \textbf{(Figure
4)}. CNS immunological dysregulation in the context of allergy and/or
glioma has been examined in multiple studies but remains poorly
characterized \textbf{(Figure 5 and Box 1)}.

\textbf{\emph{Figure 4: The border-associated immune compartments of the
brain}}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Turner-et-al--Figure-4/Turner-et-al.-Figure-5}
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{\label{158227}}%
}}
\end{center}
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\emph{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.~}\textbf{\emph{(A)}} \emph{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.}
\textbf{\emph{(B)}} \emph{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}
\textbf{\emph{(C)}} \selectlanguage{ngerman}\emph{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.
\textbf{(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.
\textbf{(E)} The circumventricular organs (CVO) are highly vascularized
areas located in the 3\textsuperscript{rd} and 4\textsuperscript{th}
ventricle. There is a communication via the blood, brain parenchyma and
CSF in the CVOs. \textbf{(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. \textbf{(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)\textsuperscript{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}

\textbf{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.\textsuperscript{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.\textsuperscript{11} Importantly, a
recent phase 3 trial has shown the efficacy of the IDH1/2 inhibitor
vorasidenib in IDH-mutant grade 2 glioma.\textsuperscript{88}{}

Efforts focusing on the antagonism of glioma-associated
immunosuppression alone, e.g., blocking the TGF\emph{-}\selectlanguage{greek}β
\selectlanguage{english}pathway\textsuperscript{89} 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
recurrent\textsuperscript{90} glioblastoma with\textsuperscript{91} or
without\textsuperscript{92} O\textsuperscript{6}-methylguanine DNA
methyltransferase (\emph{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.\textsuperscript{92} It was also not superior to placebo in
patients with tumours with \emph{MGMT} promoter methylation who may
exhibit higher mutational burden because of
chemosensitivity.\textsuperscript{91} Promising findings for survival
were observed when anti-PD-1 antibody, pembrolizumab, was administered
in a ``neoadjuvant'' setting before salvage surgery for recurrent
glioblastoma\textsuperscript{93}, though findings await confirmation in
a larger study.

Various vaccination approaches have been tested, including single
peptide-based vaccines like rindopepimut\textsuperscript{94} or
dendritic cell-based vaccines such as ICT-107\textsuperscript{95} or
DCVax\textsuperscript{96}, 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.\textsuperscript{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.

~

\textbf{4.~~~} \textbf{Epidemiological, clinical and pre-clinical
studies of allergy and glioma}

\textbf{4.1.~} \textbf{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 \textbf{(Figure 5A)}, with stronger findings for high-grade
glioma\textsuperscript{7,98-100}. Studies were often based on
\emph{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.\textsuperscript{101} These studies often took into
consideration a history of any allergy and/or specific allergies. In
contrast, in some, but not all\textsuperscript{102}, 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)\textsuperscript{103}, or there were positive associations
observed.\textsuperscript{103-105} In one study, inverse associations of
self-reported atopy history and glioma varied by
ethnicity.\textsuperscript{106} There were no clear associations between
self-reported allergy history and brain tumour risk in recent studies in
children and adolescents.\textsuperscript{107}

\textsuperscript{}{}\textbf{\emph{Figure 5: Allergic inflammation
modulation of central nervous system (CNS) homeostasis.}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Turner-et-al--Figure-41/Turner-et-al--Figure-41}
\caption{{This is a caption
{\label{634758}}%
}}
\end{center}
\end{figure}

\textbf{\emph{(A)}} \emph{Allergic diseases have typically been
inversely related to the risk of glioma development, and}
\textbf{\emph{(B)}} \emph{conversely, positively related to the risk of
neurological or psychiatric diseases.} \textbf{\emph{(C-F)}} \emph{An
extended knowledge of allergy's impact on the brain was unearthed using
rodent models of allergic disorders.} \textbf{\emph{(C)}} \emph{These
studies demonstrated that allergic inflammation could increase the level
of mRNA and cytokines from Th1/Th2 immunity,} \textbf{\emph{(D)}}
\emph{as well as of IgE and IgG in brain lysates compared to controls.
In parallel, allergic inflammation was shown to lead to activation of
brain-specific cells, such as} \textbf{\emph{(E)}} \emph{microglia and}
\textbf{\emph{(F)}} \emph{astrocytes.} \textbf{\emph{(G)}} \emph{Changes
in the resting state of spontaneous brain activity demonstrate allergic
inflammation can modulate brain homeostasis in humans}\textbf{\emph{.}}
\selectlanguage{ngerman}\emph{Created with «~BioRender.com».}\textbf{}

\par\null

There are also studies of \emph{allergy biomarkers}, such as total
and/or sIgE and glioma. For example, pre-diagnosis concentrations of
tIgE were inversely associated with glioma
occurrence.\textsuperscript{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.\textsuperscript{111}
Histamine-H4 blocking drugs may moderate CD4\textsuperscript{+} T-cell
functions away from classical allergy-associated Th2 features and
support FOXP3\textsuperscript{+}Tregs. \textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{119} ~One study reported significant inverse
associations between CCL22 and glioma risk; however CCL22 was not
associated with self-reported allergy or IgE.\textsuperscript{120}
Another study reported positive associations of sIL10RB, VEGF,
beta-Catenin and CCL22 and glioma risk among the 277 pre-diagnostic
cytokines evaluated.\textsuperscript{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 \emph{SNPs of genes related to allergy} reported
some association with either glioma or glioblastoma risk and
outcome.\textsuperscript{122} Genetic variation of HLA was related to
glioblastoma risk in a Korean study.\textsuperscript{123} ~A recent GWAS
study examined specific molecular subtypes of glioma based on \emph{IDH}
mutation, \emph{TERT} mutation, and 1p/19q codeletion
status.\textsuperscript{124} There were two new regions associated with
specific glioma subtypes including a region in \emph{D2HGDH} (which is
also associated with allergy and asthma) that was associated with
\emph{IDH}-mutant but not \emph{IDH}-wild-type
glioma.\textsuperscript{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.\textsuperscript{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.\textsuperscript{128} They suggested that
previous findings of protective effects of atopic traits may be driven
by environmental factors.

\textbf{4.2.~} \textbf{Studies of allergy and glioma prognosis}

Two studies reported better prognosis among glioma patients with \emph{a
history of allergy}; in one of these studies, this was shown to be
independent of tumour mutational status
(\emph{IDH})\textsuperscript{129,130} Prior history of asthma in
patients with glioma was associated with higher mortality
risk\textsuperscript{131}, while elevated, versus normal or borderline,
\emph{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.\textsuperscript{131,132}

Elevated serum IgE levels and past history of allergies were less
frequent in patients with glioma compared with healthy
subjects.\textsuperscript{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.\textsuperscript{134}

Associations between allergy-related cytokines/chemokines and prognosis
are generally restricted to gene polymorphisms, including in IL-4Ra and
IL -13\textsuperscript{82,135}. Allergy-related IL4R rs1805016 and
1805015 (TT genotypes) were associated with long-term survival in
high-grade glioma\textsuperscript{135} whilst IL-4R\selectlanguage{greek}α \selectlanguage{english}AA conferred
survival advantages in GBM.\textsuperscript{82} Inverse correlations
were reported between specific complement proteins and immunoglobulins
in relation to glioma grade.\textsuperscript{136} Aberrant expression of
some allergy-associated (e.g., IL-33)\textsuperscript{137} or
anti-inflammatory cytokines (e.g., IL-10\textsuperscript{138},
TGF-\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{81}), corresponded with poor prognosis.
Circulating CCL22 levels were associated with improved glioma survival,
but were unrelated to allergy history or post-diagnosis
IgE.\textsuperscript{120}

Overexpression of \emph{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.\textsuperscript{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 prognosis\textsuperscript{140}, although a separate study
found prognostic value of AEC only in low-grade glioma
(LGG).\textsuperscript{141} Eosinophil activation has been positively
linked to improved overall survival (OS)\textsuperscript{142}; and
increased AEC predicted shorter treatment duration with anti-VEGF
antibody and more favourable progression-free
survival.\textsuperscript{143} Accordingly, lower AEC correlated with
shorter OS\textsuperscript{144} and AEC falls rapidly as glioma grade
increases.\textsuperscript{145} Observations for basophils are
inconsistent and limited to a few studies.\textsuperscript{140,146} MC
activation was positively linked to OS\textsuperscript{142}, including
prognostic MC related genes in predicting survival.\textsuperscript{147}
However, increased infiltrating MCs are detectable in GBM compared to
LGG.\textsuperscript{148}

\emph{Antihistamine} usage was reported to have little impact on
survival or prognosis, although further research is
required.\textsuperscript{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.\textsuperscript{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 \textbf{(Box 2)}.

\textbf{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-\textsuperscript{150}
and high-grade gliomas\textsuperscript{151}. 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 (NF\selectlanguage{greek}κ\selectlanguage{english}B) signalling.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{4.~~~} \textbf{Future Research in AllergoOncology}

Opportunities exist for future investigation of allergy and glioma risk,
prognosis, and treatment response \textbf{(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 \textbf{(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 \textbf{(Figure 6C)}. Integrating exposome
approaches may be particularly valuable.\textsuperscript{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 IgE\textsuperscript{5} or serum
IgG4/IgE ratios\textsuperscript{153} 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.\textsuperscript{154}

Finally, in-depth understanding of cellular and molecular effects that
may be shared between allergic diseases and gliomas is needed.
Innovative \emph{in-vitro} and \emph{in-vivo} models are needed to
further elucidate potential causative molecular mechanisms and
stratification in AllergoOncology in relation to glioma \textbf{(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 \textbf{(Box 1
and Figure 5)}. \textbf{} 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.\textsuperscript{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 diseases\textsuperscript{156} and
glioma\textsuperscript{157}, the impact of immune cells with regard to
the association between both pathologies remains to be explored.

\textbf{\emph{Figure 6: Future research in AllergoOncology}}

\textbf{\emph{}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Turner-et-al--Figure6/Turner-et-al--Figure6}
\caption{{This is a caption
{\label{407440}}%
}}
\end{center}
\end{figure}

\emph{} \textbf{\emph{(A)}} \emph{This panel highlights potential
directions for future investigations into the relationship between
allergies and brain immunology in the context of gliomagenesis. Emphasis
is placed on studying glioma risk, prognosis and treatment response.}
\textbf{\emph{(B)}} \emph{Biomarker-driven analysis, utilizing current
and upcoming clinically relevant markers for allergies, can aid in
defining patient phenotypes and endotypes. Coupled with the
sub-classification of gliomas based on integrated diagnosis (refer to}
\textbf{\emph{Table 1}}\emph{), this approach holds the potential to
address various unanswered questions in the field (as described in}
\textbf{\emph{Box 2}}\emph{).} \textbf{\emph{(C)}} \emph{Next-generation
AllergoOncology studies could incorporate the use of relevant biomarkers
for allergy and glioma classification, particularly in large patient
cohorts. It is essential to establish high-resolution epidemiological
cohorts with comprehensive individual characteristics (including
demographics, medical records with comorbidity and treatment
information), as well as biospecimens (such as blood, serum, feces,
PBMC, and hair) collected over the lifetime or at etiologically relevant
time points. This will enable integrated multi-omics analysis.}
\textbf{\emph{(D)}} \emph{Innovative} \emph{in-vitro} \emph{and}
\emph{in-vivo} \emph{models are necessary to further elucidate the
causative molecular mechanisms underlying AllergoOncology.
Stratification approaches can play a crucial role in fulfilling these
research needs.} \textbf{\emph{(E)}} \selectlanguage{ngerman}\emph{The ultimate objective is to
sustain the development of innovative clinical trials aimed at advancing
new therapeutics in the field of AllergoOncology. Created with
«~BioRender.com».}

\textbf{}

\textbf{6.~~~} \textbf{Conclusion}{}

In this Position Paper, we review recent advances in allergy and glioma
heterogeneity, underlining innovative opportunities for translational
research. Future epidemiological AllergoOncology research could
capitalise upon modern atopy-related biomarkers for assessment in glioma
development and clinical outcomes and potentially elucidate underlying
molecular and cellular mechanisms. Efforts to systematically record
real-world and novel biomarkers relevant to allergy and cancer risk are
needed, including in cohorts, registries and in medical records.
Collecting atopy-related data for monitoring immunosuppression-related
changes in cancer patients is also needed. Relevant studies accounting
for immune system heterogeneity, glioma diversity, and specific allergic
conditions may provide improved insights into the complex allergy-glioma
relationship.

\par\null\par\null

\textbf{BOXES}

\textbf{Box 1: Allergic inflammation and brain physiology}

·~~~~~~~~ The Blood-Brain Barrier (BBB) is no longer the only
specialized border contributing to controlling neuro-immune crosstalk
and brain immunosurveillance \textbf{(Figure 4)}.\textsuperscript{87}{}

·~~~~~~~~ Similar roles have recently been attributed to the
circumventricular organs (CVO), skull bone marrow channels, the
meningeal lymphatic system, choroid plexus, cribriform plate and more
recently the subarachnoid lymphatic-like membrane
(SLYM).\textsuperscript{158}

·~~~~~~~~ In these structures, blood-borne resident immune cells create
specialized immune niches involved in brain development, homeostasis,
and protection.

·~~~~~~~~ Immune cells associated with T2-immunity, such as MCs, ILC2,
B-cells, and Th2-cells, can be found in these
barriers.\textsuperscript{159}

·~~~~~~~~ IL-33, IL-13, and IL-4, which are T2-immunity related soluble
factors, play a role in immune-related mechanisms associated with
neuroprotection and neuroinflammation\textsuperscript{159}, such as
modulating synaptic remodelling and activity.\textsuperscript{160,161}{}

·~~~~~~~~ Existing evidence suggests that peripheral allergic
inflammation affects brain homeostasis \textbf{(Figure
5)}.\textsuperscript{162}

·~~~~~~~~ Allergic sensitization in rodent models leads to rapid
activation of neuronal pathways\textsuperscript{163,164}, as well as
Th1- and Th2-related gene expression\textsuperscript{165,166}, and
accumulation of IgG and IgE in the brain
parenchyma.\textsuperscript{167,168}

·~~~~~~~~ Studies have shown that peripheral allergic inflammation in
mouse models can activate microglia into a pro-inflammatory state
induced with either timothy grass pollen\textsuperscript{169},
ovalbumin\textsuperscript{170}, fungal allergens\textsuperscript{171} or
house dust mite.\textsuperscript{151}

·~~~~~~~~ Mice with asthma or AD demonstrate increased activation of
microglia and astrocytes in the spinal cord.\textsuperscript{170}

·~~~~~~~~ Epigenetic changes have been detected in microglia obtained
from the offspring of mothers with allergic asthma.\textsuperscript{172}

·~~~~~~~~ Emerging studies are investigating differences in brain
activity between allergic and non-allergic
individuals.\textsuperscript{173,174}

\textsuperscript{}{}

\textbf{BOX 2: Research questions for new studies in allergy and glioma
risk, prognosis, and treatment}

·~~~~~~~~ What are the most relevant and promising new allergy
biomarkers for future AllergoOncology studies in glioma?

·~~~~~~~~ What is the most relevant allergic phenotype, genotype, or
endotype for glioma?

·~~~~~~~~ Is the association of allergy and glioma most relevant for a
specific glioma subtype?

·~~~~~~~~ What is the association of allergy and glioma in large-scale
prospective studies with comprehensive and objectively measured allergy
biomarkers across the lifecourse using both systematic and agnostic
analysis methods?

·~~~~~~~~ Are tIgE and/or sIgE involved in glioma immunosurveillance and
or immunoediting? What are the optimal threshold of IgE concentration?

·~~~~~~~~ What is the association of allergy and glioma in broader
geographically diverse populations with different genetic backgrounds
and environmental exposures?

·~~~~~~~~ What is the impact of climate-related changes in allergen
exposure, allergy and glioma?

·~~~~~~~~ What is the impact of anti-allergic therapies (including AIT),
including their interactions, in allergy and glioma?

·~~~~~~~~ What are the most relevant allergy biomarkers for monitoring
immune-glioma interactions and treatment response?

·~~~~~~~~ Can next generation AllergoOncology research develop an
allergy-related immunoscore for the prediction of recurrence and/or
response to therapeutics?

·~~~~~~~~ How can patient records, registries, and databases capture the
most relevant AllergoOncology data for future research?

·~~~~~~~~ What is the impact of allergy on brain immunology in the
context of glioma?

·~~~~~~~~ Does the phenomenon of trained immunity, which is associated
with the initiation of allergic diseases or influenced by allergic
responses, exhibit a distinguishable and specific role in the process of
glioma elimination? Can improved allergy and glioma therapeutic options
be developed based on findings in AllergoOncology?

Is research and knowledge of allergic disorders and glioma relevant to
other priority cancer types?

\textbf{TABLES}

\textbf{Table 1: Selected biomarkers and individual demographics to
study links between allergic diseases and gliomas}.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table1-picture/Table1-picture}
\caption{{This is a caption
{\label{978643}}%
}}
\end{center}
\end{figure}



\textbf{Table 2: Biological drugs targeting molecules relevant for
atopic/allergic disease pathomechanisms.} ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Target} & \textbf{Indication} & \textbf{Drug} &
\textbf{~}\tabularnewline
IL-5 receptor (CD125) & Asthma & Benralizumab & ~\tabularnewline
Inhibits the dimerization of IL-13R\selectlanguage{greek}α\selectlanguage{english}1 and IL-4R\selectlanguage{greek}α & Asthma + AD &
Lebrikizumab & *\tabularnewline
IL-5 & Asthma & Mepolizumab & ~\tabularnewline
IL-5 R\selectlanguage{greek}α & Asthma & Reslizumab & ~\tabularnewline
IgE & Asthma + Urticaria & Omalizumab & ~\tabularnewline
IL-4 R\selectlanguage{greek}α \selectlanguage{english}subunit & AD, Asthma, CRSwNP & Dupilumab & ~\tabularnewline
IL-9 & Asthma{} & Enokizumab & *\tabularnewline
IL-13 & AD & Tralokinumab & ~\tabularnewline
IL-33 & AD & Etokimab & ~\tabularnewline
IL-31 receptor A & AD & Nemolizumab & ~\tabularnewline
TSLP & Tezepelumab & Tezepelumab & ~\tabularnewline
IgE & Chronic urticaria & Ligelizumab & ~\tabularnewline
IgE & Chronic urticaria, Asthma, CRSwNP & Omalizumab & ~\tabularnewline
Lectin 8 & Asthma & Lirentelimab & ~\tabularnewline
Inhibits JAK1 and JAK2 & AD & Baricitinib & ~\tabularnewline
JAK1 inhibitor & AD & Upadacitinib & ~\tabularnewline
JAK1 inhibitor & AD & Abrocitinib & ~\tabularnewline
A CRTH2 antagonist & Th2-mediated inflammation & AMG853 &
*\tabularnewline
A CRTH2 antagonist & Th2-mediated inflammation &
\href{https://www.ncbi.nlm.nih.gov/nuccore/OC000459}{OC000459}{} &
*\tabularnewline
A CRTH2 antagonist & Th2-mediated inflammation &
\href{https://www.ncbi.nlm.nih.gov/nuccore/BI671800}{BI671800}{} &
*\tabularnewline
Inhibitor of GSNOR & Th2-mediated inflammation & N6022 &
*\tabularnewline
Plasma kallikrein & Hereditary angioedema & Lanadelumab &
~\tabularnewline
\bottomrule
\end{longtable}

Adapted from Guelsen et al., 2020\textsuperscript{30}, modified and
updated \textsuperscript{31}. *Studies ongoing

~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~

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