Cord blood natural killer cells expressing a dominant negative TGF-ß receptor: Implications for adoptive immunotherapy for glioblastoma.
Cytotherapy
; 19(3): 408-418, 2017 03.
Article
in En
| MEDLINE
| ID: mdl-28109751
ABSTRACT
Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-ß). We observed that TGF-ß inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-ß, we engrafted a dominant negative TGF-ß receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-ß. After manufacture using Good Manufacturing Practice-compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-ß allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-ß-secreting tumors and may be an important therapeutic approach for patients with cancer.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Killer Cells, Natural
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Genetic Therapy
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Immunotherapy, Adoptive
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Protein Serine-Threonine Kinases
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Receptors, Transforming Growth Factor beta
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Glioblastoma
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Fetal Blood
Limits:
Humans
Language:
En
Journal:
Cytotherapy
Journal subject:
TERAPEUTICA
Year:
2017
Document type:
Article