Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells.
Animals
Female
Glioblastoma
/ genetics
Heterografts
Humans
Integrins
/ genetics
Killer Cells, Natural
/ immunology
Male
Mice
Neoplasm Proteins
/ genetics
Neoplasm Transplantation
Neoplastic Stem Cells
/ immunology
Receptor, Transforming Growth Factor-beta Type II
/ genetics
Transforming Growth Factor beta
/ genetics
Brain cancer
Cancer immunotherapy
Immunology
NK cells
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
received:
09
07
2020
accepted:
03
06
2021
pubmed:
18
6
2021
medline:
13
10
2021
entrez:
17
6
2021
Statut:
ppublish
Résumé
Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.
Identifiants
pubmed: 34138753
pii: e142116
doi: 10.1172/JCI142116
pmc: PMC8279586
doi:
pii:
Substances chimiques
ITGA5 protein, human
0
Integrins
0
Neoplasm Proteins
0
Transforming Growth Factor beta
0
Receptor, Transforming Growth Factor-beta Type II
EC 2.7.11.30
TGFBR2 protein, human
EC 2.7.11.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127001
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA120813
Pays : United States
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