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Glioblastoma stem cell metabolism and immunity

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Abstract

Despite enormous efforts being invested in the development of novel therapies for brain malignancies, there remains a dire need for effective treatments, particularly for pediatric glioblastomas. Their poor prognosis has been attributed to the fact that conventional therapies target tumoral cells, but not glioblastoma stem cells (GSCs). GSCs are characterized by self-renewal, tumorigenicity, poor differentiation, and resistance to therapy. These characteristics represent the fundamental tools needed to recapitulate the tumor and result in a relapse. The mechanisms by which GSCs alter metabolic cues and escape elimination by immune cells are discussed in this article, along with potential strategies to harness effector immune cells against GSCs. As cellular immunotherapy is making significant advances in a variety of cancers, leveraging this underexplored reservoir may result in significant improvements in the treatment options for brain malignancies.

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Abbreviations

GSCs:

Glioblastoma stem cells

GBM:

Glioblastoma multiforme

pGBM:

Pediatric glioblastoma multiforme

SEER:

Surveillance, Epidemiology, and End Results Program

GTR:

Gross total resection

WHO:

World Health Organization

IARC:

International Agency for Research on Cancer

RF-EMF:

Radiofrequency electromagnetic fields

H3F3A:

H3.3 histone A gene

G34R/V:

Denotes the substitution of a glycine amino acid at position 34 with either arginine or valine

IDH1:

Isocitrate dehydrogenase 1

2-HG:

2-Hydroxyglutarate

TP53:

Tumor protein p53

17p13.1:

Sub-band 1 of band 3 of region 1 of the short arm of chromosome 17

PMS2:

PMS1 (postmeiotic segregation increased 1) homolog 2, mismatch repair system component

EGFRA:

Epidermal growth factor receptor A

EGFR:

Epidermal growth factor receptor

ATRX:

Alpha thalassemia X-linked intellectual disability

RB:

Retinoblastoma

MRI:

Magnetic resonance imaging

CSC:

Cancer stem cell

NSC:

Neural stem cells

SVZ:

Subventricular zone

AML:

Acute myeloid leukemia

MYC:

Myelocytomatosis oncogene

BAD:

BCL-2 (B cell leukemia/lymphoma 2)-associated agonist of cell death

NK:

Natural killer cell

DCs:

Dendritic cells

CTLs:

Cytotoxic T Lymphocytes

Th cells:

Helper CD4+ T cells

TNF:

Tumor necrosis factor

NCRs:

Natural cytotoxicity receptors

NKp30:

Natural cytotoxicity triggering receptor 3

NKp44:

Natural cytotoxicity triggering receptor 2

NKp46:

Natural cytotoxicity triggering receptor 1

CD336:

Cluster of differentiation 336

PCNA:

Proliferating cell nuclear antigen

B7H6:

Natural killer cell cytotoxicity receptor 3 ligand 1

MHC:

Major histocompatibility complex

NKG2A:

NKG2-A/NKG2-B type II integral membrane protein-like

HLA:

Human leukocyte antigen

DNAM-1:

DNAX (DNA polymerase III subunit gamma) accessory molecule

NKG2D:

Natural killer group 2 member D protein

MICA/B:

MHC class I polypeptide-related sequence A/B

ULBP:

UL16-binding protein

ADCC:

Antibody-dependent cellular cytotoxicity

FasL:

Fas ligand

TRAIL:

TNF superfamily member 10

DR4:

Death receptor 4

DR5:

Death receptor 5

IFN-γ:

Interferon gamma

KIRs:

Killer cell immunoglobulin-like receptors

Tregs:

Regulatory T cells

MDSCs:

Myeloid-derived suppressor cells

KLRK1:

Killer cell lectin-like receptor K1

PROM:

Prominin-1 gene

mRNA:

Messenger ribonucleic acid

CD133:

Cluster of differentiation 133

THPA:

The Human Protein Atlas

DAMPS:

Damage-associated molecular patterns

PRRs:

Pattern recognition receptors

TLRs:

Toll-like receptors

NOD:

Nucleotide binding oligomerization domain

TME:

Tumor microenvironment

IL-2:

Interleukin 2

PDL1:

Programmed cell death ligand 1

CTLA:

Cytotoxic T lymphocytes associated protein

TGF-β:

Transforming growth factor-beta

IL-10:

Interleukin 10

IL-6:

Interleukin 6

IDO1:

Indoleamine-2,3-dioxygenase-1

TAM:

Tumor-associated macrophage

pLGG:

Pediatric low grade glioma

pHGG:

High-grade gliomas

DIPG:

Diffuse intrinsic pontine glioma

Th1 cells:

Type 1 T helper cells

G34R:

Denotes the substitution of a glycine amino acid at position 34 with arginine

K27M:

Denotes the substitution of a lysine amino acid at position 27 with methionine

CXCR2:

C-X-C motif chemokine receptor 2

RNA:

Ribonucleic acid

OXPHOS:

Oxidative phosphorylation

NANOG:

Nanog homeobox

OCT4:

Octamer-binding transcription factor 4

SOX4:

SRY (sex determining region of chr Y)-box transcription factor 4

GLUT1:

Glucose transporter 1

mTORC1:

MTOR (mammalian target of rapamycin) complex 1

HIF-1α:

Hypoxia-inducible factor 1 subunit alpha

HK2:

Hexokinase 2

PKM2:

Pyruvate kinase M2

MCT1:

Monocarboxylate transporter 1

SLC16A1:

Solute carrier family 16 member 1

MCT4:

Monocarboxylate transporter 4

SLC16A3:

Solute carrier family 16 member 3

PDK1:

Pyruvate dehydrogenase kinase 1

PFKFB4:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4

DNA:

Deoxyribonucleic acid

ROS:

Reactive oxygen species

PGC-1α:

Proliferator-activated receptor-gamma coactivator-1α

IMP2:

Marker insulin-like growth factor 2

NDUFS3:

NADH (nicotinamide adenine dinucleotide + hydrogen) ubiquinone oxidoreductase core subunit S3

NDUFS7:

NADH (nicotinamide adenine dinucleotide + hydrogen) ubiquinone oxidoreductase core subunit S7

NDUF3:

NADH:ubiquinone oxidoreductase complex assembly factor 3

RIP-ChIP:

RNA-binding protein immunoprecipitation-chromatin immunoprecipitation

U87MG:

Uppsala 87 Malignant Glioma

ATP:

Adenosine triphosphate

FAO:

Fatty acid oxidation

CD47:

Cluster of differentiation 133

SP1:

Specificity protein 1

SREBP1:

Sterol regulatory element-binding protein 1

SMCT2:

Sodium-coupled monocarboxylate transporter 2

SLC5A12:

Solute carrier family 5 (sodium/glucose cotransporter), member 12

p38:

P38 kinase

Jnk:

C-Jun NH2-terminal kinase

c-Jun:

Jun proto-oncogene

ERK:

Extracellular signal-regulated MAP kinase

STAT3:

Signal transducer and activator of transcription 3

NF-κB:

Nuclear factor of kappa B

JAK:

Janus kinase

BCL-XL:

B-cell lymphoma extra-large

MMPs:

Matrix metalloproteinases

VEGF:

Vascular endothelial growth factor

Foxp3:

Forkhead box P3 (FOXP3) protein

PI3K:

Phosphatidylinositol 3-kinase

AKT:

Protein kinase B

ALDH:

Aldehyde dehydrogenase

MAPK:

Mitogen-activated kinase-like protein

CARs:

Chimeric antigen receptors

PD1:

Programmed cell death 1

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

BiKEs:

Bi-specific killer engagers

TriKEs:

Tri-specific killer engagers

αPD1:

Anti-PD1 antibody

αCTLA4:

Anti-CTLA4 antibody

IL-1β:

Interleukin-1 beta

TNF-α:

Tumor necrosis factor alpha

FOXO3:

Forkhead box O3 gene

AMPK:

Adenosine monophosphate-activated protein kinase

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  1. Alejandro Schcolnik-Cabrera and Mark E. Issa contributed equally to this work.

Authors and Affiliations

  1. Faculty of Medicine and Medical Sciences, University of Balamand, Dekouaneh, Lebanon

    Joseph Hawly

  2. Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA

    Micaela G. Murcar & Mark E. Issa

  3. Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB, Canada

    Alejandro Schcolnik-Cabrera

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MEI: conceptualization; JH, MM, ASC, and MEI: resource collection, writing, and figure preparation; ASC and MEI: design and reviewing of the manuscript. All the authors have approved the final version of the manuscript.

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Hawly, J., Murcar, M.G., Schcolnik-Cabrera, A. et al. Glioblastoma stem cell metabolism and immunity. Cancer Metastasis Rev (2024). https://doi.org/10.1007/s10555-024-10183-w

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