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- Title
Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.
- Authors
Lian, Guang-Yu; Wang, Qing-Ming; Mak, Thomas Shiu-Kwong; Huang, Xiao-Ru; Yu, Xue-Qing; Lan, Hui-Yao
- Abstract
Through Smad3-dependent signalings, transforming growth factor-β (TGF-β) 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-β-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-β-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.
- Subjects
KILLER cells; GRANULOCYTE-macrophage colony-stimulating factor; CELL physiology; CANCER cells; T cells; NEUTROPHILS; CYTOTOXINS; VOXEL-based morphometry; BREAST
- Publication
Cellular & Molecular Life Sciences, 2024, Vol 81, Issue 1, p1
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-024-05290-4