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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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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DOI: https://doi.org/10.1007/s10555-024-10183-w