Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells.
Qing-Ming WangPatrick Ming-Kuen TangGuang-Yu LianChunjie LiJinhong LiXiao-Ru HuangKa-Fai ToHui Yao LanPublished in: Cancer immunology research (2018)
Natural killer (NK) cells, early effectors in anticancer immunity, are paralyzed by TGFβ1, 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 TGFβ1-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.
Keyphrases
- nk cells
- papillary thyroid
- transforming growth factor
- epithelial mesenchymal transition
- squamous cell
- endothelial cells
- genome wide
- immune response
- dendritic cells
- copy number
- signaling pathway
- cell proliferation
- induced apoptosis
- cell death
- transcription factor
- cell cycle arrest
- young adults
- long non coding rna
- pluripotent stem cells
- genome wide identification
- basal cell carcinoma