Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.
Cell Mol Life Sci
; 81(1): 262, 2024 Jun 15.
Article
in En
| MEDLINE
| ID: mdl-38878186
ABSTRACT
Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Killer Cells, Natural
/
Granulocyte-Macrophage Colony-Stimulating Factor
/
Smad3 Protein
/
Lung Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Mol Life Sci
Journal subject:
BIOLOGIA MOLECULAR
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: