1. Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.
- Author
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Lian GY, Wang QM, Mak TS, Huang XR, Yu XQ, and Lan HY
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Cell Line, Tumor, Dendritic Cells immunology, Dendritic Cells metabolism, Transforming Growth Factor beta metabolism, Cell Differentiation, Macrophages metabolism, Macrophages immunology, Signal Transduction, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Smad3 Protein metabolism, Smad3 Protein genetics, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms metabolism, Lung Neoplasms genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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