Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells.
Cancer Immunol Res
; 6(8): 965-977, 2018 08.
Article
in En
| MEDLINE
| ID: mdl-29915022
ABSTRACT
Natural killer (NK) cells, early effectors in anticancer immunity, are paralyzed by TGFß1, an immunosuppressive cytokine produced by cancer cells. Development and activity of NK cells are largely inhibited in the Smad3-dependent tumor microenvironment. Here, we used genetic engineering to generate a stable SMAD3-silencing human NK cell line, NK-92-S3KD, whose cancer-killing activity and cytokine production were significantly enhanced under TGFß1-rich condition compared with the parental cell line. Interestingly, we identified that the IFNG gene is a direct E4BP4 target gene. Thus, silencing of SMAD3 allows upregulation of E4BP4 that subsequently promoting interferon-γ (IFNγ) production in the NK-92-S3KD cells. More importantly, NK-92-S3KD immunotherapy increases the production of not only IFNγ, but also granzyme B and perforin in tumors; therefore, inhibiting cancer progression in two xenograft mouse models with human hepatoma (HepG2) and melanoma (A375). Thus, the NK-92-S3KD cell line may be useful for the clinical immunotherapy of cancer. Cancer Immunol Res; 6(8); 965-77. ©2018 AACR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Melanoma, Experimental
/
Killer Cells, Natural
/
Smad3 Protein
/
Immunotherapy
/
Liver Neoplasms, Experimental
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Immunol Res
Year:
2018
Document type:
Article
Affiliation country:
China